Methods of treating diabetes

Abstract

The specification relates to the administration of small molecule, once-daily, oral glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus.

Description

[0001] METHODS OF TREATING DIABETES

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application 63 / 715,300, filed November 1, 2024, which is incorporated by reference herein in its entirety for all purposes.

[0004] BACKGROUND

[0005] Glucagon-like peptide- 1 receptor agonists (GLP-1 RAs) are currently approved therapies for T2DM and obesity. GLP-1 RAs mimic the effects of the natural hormone glucagon-like peptide- 1 (GLP-1) in the body by potentiating insulin secretion at high glucose levels, suppressing glucagon release, inhibiting gastric emptying, and promoting satiety, leading to improved glycemic control and reductions in bodyweight. GLP-1 RAs have also been shown to improve pancreatic P-cell function, protect P-cells against apoptosis and promote their regeneration. To date, GLP-1RA have established clinical benefit in treating patients with type 2 diabetes mellitus (T2DM) and obesity. Therapeutically, several highly potent GLP-lRAs have been approved, including albiglutide, dulaglutide, exenatide, exenatide extended-release, liraglutide, luxisenatide, and semaglutide.

[0006] However, most approved GLP-1 RAs are injectable peptides that require a cold chain supply and storage. Typically, these injectable treatments are once-weekly treatments and, in some cases, require a slow up-titration or dose escalation period in order to achieve therapeutic efficacy. Currently, semaglutide (Rybelsus®) is the only GLP-1 RA that is available as a once- daily oral tablet. However, the approved oral doses cannot achieve the higher drug exposures of injectable semaglutide to deliver equivalent reductions in body weight and glucose level. Additionally, oral semaglutide has a complex dosing regimen that requires prior fasting and a gap of at least 30 minutes without food or other medications to ensure proper absorption.

[0007] Additionally, both peptide and small molecule GLP-1 RAs have significant gastrointestinal side-effects, even at low doses, and require slow require a slow up-titration or dose escalation period in order to achieve therapeutic efficacy. These side effects are also the most common reason for patients discontinuing treatment. Therefore, barriers to GLP-1 RA therapy still exist for patients, and there is a need for small molecule GLP-1 RA that can greatly enhance patient access and provide therapeutic efficacy with minimal side effects and fewer, or no, up-titration steps.

[0008] GLP-lRAs reduce body weight, improve glucose control, and lead to improved cardiovascular outcomes. AZD5004 (ECC5004) is a novel small molecule GLP-1 RA for use as an oral therapy for chronic weight management and T2DM. Preclinical studies with AZD5004 have demonstrated its chemical characteristics and potency in lowering plasma glucose.

[0009] DESCRIPTION OF FIGURES

[0010] Figure 1: In vitro profiling of AZD5004 on the hGLP-lR. AZD5004 potently binds the human GLP-1R (A) triggering downstream signaling through cAMP in HEK-293 cells (B) and CHO-K1 cells (C). Binding of AZD5004 to the receptor does not lead to P-arrestin-2 recruitment (C) or receptor internalization (D), while GLP-1 (7-36)NH2 potently activates both signaling events. AZD5004 concentration-dependently potentiated insulin secretion at 11 mM glucose in EndoC- |3H5 cells (E). Curves are derived from three independent test occasions and error bars represent SEM for responses at each concentration, except for (A) and (B) where one representative curve is shown. Data from each assay is presented as percentage of the positive control used in the assay. Potency data and positive controls used are summarized in Table 1.

[0011] Figure 2: PK / PD assessment in NHPs. AZD5004 showed a dose-dependent effect on cAMP in a cell line overexpressing the cynomolgus GLP-1R (A). AZD5004 presented a favorable PK profile with a half-life of 1.72 ± 0.405 hours (mean ± SD) and plasma clearance of 14.7±1.32 mL / min / kg (mean ± SD) in lean NHPs following a single intravenous dose (0.5 mg / kg) (B). AZD5004 potentiated insulin secretion following an IVGTT in obese NHPs as exemplified by the effect on insulin following 33 pg / kg intravenous of AZD5004 compared to vehicle administered before the glucose bolus (0.5 g / kg) (C). From the insulin profiles measured following the six different doses of AZD5004 evaluated, an AUC was calculated for each dose and plotted against the corresponding free average exposure of AZD5004 (PK / PD plot) (D). From the PK / PD data an in vivo potency of 0.022 nM (ECso) was estimated. Abbreviations: AUC, area under concentration-time curve; IVGTT, intravenous glucose tolerance tests; NHP, non-human primates; PD, pharmacodynamics; PK, pharmacokinetics; SD, standard deviation. Figure 3: Chronic NHP toxicity study. Upper panel shows the body weight over time for the female and male NHPs with the median effect in bold. During the dose titration (dose escalation) period from day -14 to day 0, the low- and mid-dose groups received AZD5004 10 and 30 mg / kg / day, respectively. The high-dose group was administered AZD5004 30 mg / kg / day for 14 days and 50 mg / kg / day from day 1 and beyond. The lower panel shows LS mean (darker line) of AZD5004 dose-dependent decreased body weight gain versus control in low-, mid- and high dose groups over time in both females and males including 95% Cis (shaded area). Mean and 95% CI were obtained from an MMRM analysis. Abbreviations: CI, confidence interval;

[0012] MMRM, mixed-models for repeated measures.

[0013] Figure 4: Study Design. The Study Design for Part 1 and Part 2 of the SAD and MAD studies. A / P, active / placebo, active; MAD, multiple ascending dose; QD = once daily; SAD, single ascending dose, OGTT=oral glucose tolerance test; MMTT = mixed-meal tolerance test.

[0014] Figure 5: Pharmacokinetic analysis - SAD study. Plasma concentration profiles of AZD5004 at doses from 1 mg to 300 mg in the SAD study in healthy volunteers. Plasma concentration profiles were normalized by individual’s body weight at baseline. One participant in the 300 mg group had a missing PK data point at 48 hours post-dose.

[0015] Figure 6: AUCO-2 for glucose (A) and insulin (B) - SAD study. Top panels are changes in OGTT glucose (A) and insulin (B) AUCO-2 levels on day -1 to day 1. Bottom panels are corresponding percent changes. Darker lines represent median. Lighter lines represent individual observations. Abbreviations: AUCO-2, area under the plasma concentration-time curve from time 0 to 2 hours post-dose; CI, confidence interval; LS, least squares; D, day; OGTT, oral glucose tolerance test; SAD, single ascending dose.

[0016] Figure 7: AZD5004 pharmacodynamic profile - MAD study. Change from baseline are shown for fasting plasma glucose levels (mg / dL) (Panel A), glucose AUCO-4 (hxmg / dL) (Panel B), insulin (Panel C), C peptide (Panel D), glucagon AUC0-4 (Panel E), and percent body weight (Panel F). Dashed navy-blue lines represent placebo. Solid colored lines represent ECC5004 treatment. Darker colored lines represent median per timepoint. Panel C, D, E bottom panel, and Panel F, show percent change from Day -1 to Day 28. Solid lines represent median. A, active; AUCO-4: area under the plasma-concentration curve from time zero to 4 hours post-dose; CI, confidence interval; D, day; L, least squares; MMTT, mixed meal tolerance test; P, placebo. A, active; AUCO-4: area under the plasma-concentration curve from time zero to 4 hours post-dose; CI, confidence interval; D, day; L, least squares; MMTT, mixed meal tolerance test; P, placebo.

[0017] Figure 8: Fed / Fasted Trial Results. Study Design (A). Individual concentration-time pharmacokinetic profiles (B). Food effect analysis (C).

[0018] Figure 9: T2DM Study Design. Matched placebo denotes 6 matching placebo arms with 72 participants in total; n, number of participants; Q2W, every 2 weeks; Q4W, every 4 weeks; R, randomization.

[0019] DETAILED DESCRIPTION

[0020] Numeric ranges used herein are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0021] The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10 percent, up or down (higher or lower).

[0022] The term “initial HbAlc” refers to the subject’s HbAlc before the patient begins treatment with AZD5004, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject may have previously on another HbAlc lowering treatment, in which case “initial HbAlc” refers to the subject’s HbAlc level without any treatment. In certain embodiments the “initial dose” or “initial once-daily dose” refers to the first once- daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, administered to a subject beginning treatment with AZD5004, or a pharmaceutically acceptable salt thereof. In certain embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered on a dose escalation schedule, wherein the once-daily doses of AZD5004, or a pharmaceutically acceptable salt thereof, are increased over a period of time, e.g., increased one, two, three, four, five, or six times every week, every two weeks, every three weeks, or every four weeks, and initial once- daily dose refers to the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof. In other embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered without any dose escalation, and the initial once-daily dose is also the target once- daily dose. One of skill in the art would understand that initial once-daily dose and first once- daily dose in the case of a subject who has previously been treated with AZD5004, or a pharmaceutically acceptable salt thereof, but has discontinued treatment for a period of time, refers to the initial once-daily dose and first once-daily dose in the current treatment with AZD5004, or a pharmaceutically acceptable salt thereof, the subject is undergoing.

[0023] In certain embodiments the “target dose” or “target once-daily dose” refers to the final once- daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, in a dose escalation schedule. In certain embodiments, the target once-daily dose refers to the final once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof. In some embodiments the target dose is the highest dose of AZD5004, or a pharmaceutically acceptable salt thereof, administered to the subject. In other embodiments the target dose is the highest tolerated dose of AZD5004, or a pharmaceutically acceptable salt thereof, administered to the subject. Target dose can also be referred to as the “maintenance dose” or the “maintenance once-daily dose”.

[0024] The terms “major cardiovascular events” or “major adverse cardiovascular events (MACE)” include cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

[0025] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. In certain embodiments subjects are humans. In further embodiments, subjects are adult humans.

[0026] AZD5004 Dosing Schedules

[0027] AZD5004, also known as ECC5004, refers to a compound with the chemical name 3-(l-(2- ((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-

[0028] 7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-l,2,4-oxadiazol-5(4H)- one, and the structure shown below:

[0029] AZD5004 is a small molecule GLP-1 RA currently in clinical trials. The synthesis of AZD5004 is described in US Patent No. 11,584,751, the contents of which are hereby incorporated by reference in their entirety for all purposes.

[0030] In certain embodiments disclosed herein, AZD5004, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof. In other embodiments disclosed herein, AZD5004 is administered to a subject in need thereof. In yet other embodiments disclosed herein, a pharmaceutically acceptable salt of AZD5004 is administered to a subject in need thereof. In still other embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered orally to a subject in need thereof. In particular embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is in an oral dosage form. In particular embodiments the oral dosage form is a tablet or capsule. In particular embodiments the oral dosage form is a tablet.

[0031] In certain embodiments of any of the methods disclosed herein, pharmaceutically acceptable salt of AZD5004 is administered to a subject in need thereof, wherein the dose of the pharmaceutically acceptable salt is based on AZD5004 not in salt form. For example, a 5 mg dose of a pharmaceutically acceptable salt of AZD5004 contains 5 mg of AZD5004 not in salt form. Phase 1 Clinical Trials of AZD5004 included single ascending dose (SAD), multiple ascending dose (MAD), and food effects studies. These studies indicated AZD5004 engages the GLP-1R and is suitable for once-daily dosing. Additionally, without being bound by the following, these trials suggest that AZD5004 can be dosed at levels predicted to be therapeutically efficacious at glucose lowering without up-titration and associated with a low frequency of GI side effects.

[0032] Disclosed herein are methods of administering AZD5004, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In other embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof on a flat dosing schedule without dose escalation or up-titration, wherein the initial once-daily dose is the target once-daily dose. In yet other embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof on a dose escalation schedule, wherein the target once-daily dose is greater than the initial once-daily dose.

[0033] In certain embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered under fed or fasted conditions. In certain embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered under fed conditions. In certain embodiments, AZD5004, or a pharmaceutically acceptable salt thereof, is administered under fasted conditions. The flat dosing schedules and escalating dose schedules disclosed herein can be administered for treating or preventing any of the indications or conditions disclosed herein, including but not limited to: type 2 diabetes mellitus (T2DM), treating chronic kidney disease (CKD), lowering HbAlC, lowering or maintaining BMI or body weight, reducing the risk of major adverse cardiovascular events, improving outcomes in subjects with CKD, and improving glycemic control. In certain embodiments, subjects have T2DM.

[0034] Flat Dosing Schedules

[0035] Disclosed herein are methods of administering AZD5004, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, according to a dosing schedule comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof. In certain embodiments, the dosing schedule comprises administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein administration occurs without a period of dose escalation. In other embodiments, the dosing schedule comprises administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein administration occurs without a period of dose escalation and the once-daily dose is once-daily dose is therapeutically effective.

[0036] Some embodiments disclosed herein provide a method of administering AZD5004, or a pharmaceutically acceptable salt thereof, to a subject in need thereof comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is from 2.5 mg to 50 mg. In certain embodiments, the subject is administered an initial once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the initial once-daily dose is therapeutically effective. In certain embodiments, therapeutically effective means any combination of the following: therapeutically efficacious glucose lowering, improved glycemic control, body weight loss, lowered HbAlc, and reduced risk of major adverse cardiovascular events.

[0037] Some embodiments disclosed herein provide a method of treating type 2 diabetes in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once- daily dose is from 2.5 mg to 5 mg, 2.5 mg to 7.5 mg, 2.5 mg to 10 mg, 2.5 mg to 12.5 mg, 2.5 mg to 15 mg, 2.5 mg to 17.5 mg, 2.5 mg to 20 mg, 2.5 mg to 22.5 mg, 2.5 mg to 25 mg, 2.5 mg to 27.5 mg, 2.5 mg to 30 mg, 5 mg to 7.5 mg, 5 mg to 10 mg, 5 mg to 12.5 mg, 5 mg to 15 mg, 5 mg to 17.5 mg, 5 mg to 20 mg, 5 mg to 22.5 mg, 5 mg to 25 mg, 5 mg to 27.5 mg, 5 mg to 30 mg, 7.5 mg to 10 mg, 7.5 mg to 12.5 mg, 7.5 mg to 15 mg, 7.5 mg to 17.5 mg, 7.5 mg to 20 mg,

[0038] 7.5 mg to 22.5 mg, 7.5 mg to 25 mg, 7.5 mg to 27.5 mg, 7.5 mg to 30 mg, 10 mg to 12.5 mg, 10 mg to 15 mg, 10 mg to 17.5 mg, 10 mg to 20 mg, 10 mg to 22.5 mg, 10 mg to 25 mg, 10 mg to

[0039] 27.5 mg, 10 mg to 30 mg, 12.5 mg to 15 mg, 12.5 mg to 17.5 mg, 12.5 mg to 20 mg, 12.5 mg to

[0040] 22.5 mg, 12.5 mg to 25 mg, 12.5 mg to 27.5 mg, 12.5 mg to 30 mg, 15 mg to 17.5 mg, 15 mg to 20 mg, 15 mg to 22.5 mg, 15 mg to 25 mg, 15 mg to 27.5 mg, 15 mg to 30 mg, 17.5 mg to 20 mg, 17.5 mg to 22.5 mg, 17.5 mg to 25 mg, 17.5 mg to 27.5 mg, 17.5 mg to 30 mg, 20 mg to

[0041] 22.5 mg, 20 mg to 25 mg, 20 mg to 27.5 mg, 20 mg to 30 mg, 22.5 mg to 25 mg, 22.5 mg to 27.5 mg, 22.5 mg to 30 mg, 25 mg to 27.5 mg, 25 mg to 30 mg, or 27.5 mg to 30 mg.

[0042] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is from 2.5 mg to 30 mg.

[0043] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is from 5 mg to 25 mg.

[0044] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is from 5 mg to 15 mg. Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is selected from 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, or 30 mg.

[0045] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is selected from 5 mg, 15 mg, and 25 mg.

[0046] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is from 2.5 mg to 100 mg.

[0047] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is from 5 mg to 75 mg.

[0048] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is selected from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 55 mg, 65 mg, and 75 mg.

[0049] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein administration occurs without dose escalation.

[0050] Escalating Dose Schedules

[0051] Some embodiments disclosed herein provide a method of administering AZD5004, or a pharmaceutically acceptable salt thereof, to a subject in need thereof comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the method comprises an escalating dosing regimen followed by a target dosing regimen. In certain embodiments, the escalating dosing regimen comprises at least two consecutive dosing periods wherein each dosing period comprises administering a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, to the subject, for a period of 1 to 4 weeks, wherein in each subsequent dosing period the once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is higher than the once-daily dose of the previous dosing period. In certain embodiments, the target dosing regimen comprises administering to the subject a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is therapeutically effective. In certain embodiments, therapeutically effective means any combination of the following: therapeutically efficacious glucose lowering, improved glycemic control, body weight loss, lowered HbAlc, and reduced risk of major adverse cardiovascular events.

[0052] Some embodiments disclosed herein provide a method of treating Tin a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the method comprises an escalating dosing regimen followed by a target dosing regimen.

[0053] Some embodiments disclosed herein provide a method of treating chronic kidney disease (CKD) in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the method comprises an escalating dosing regimen followed by a target dosing regimen. Some embodiments disclosed herein provide a method of a method of lowering HbAlc in a subject in need thereof, comprising administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the method comprises an escalating dosing regimen followed by a target dosing regimen.

[0054] In certain embodiments, the escalating dosing regimen comprises at least two consecutive dosing periods wherein each dosing period comprises administering a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a period of 1 to 4 weeks, wherein in each subsequent dosing period the once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, is 1.25 to 2.5 times the once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, of the immediately prior dosing period. In certain embodiments, each consecutive dosing period is 1 week. In other embodiments, each consecutive dosing period is 2 weeks. In still other embodiments, each consecutive dosing period is 3 weeks. In yet other embodiments, each consecutive dosing period is 4 weeks.

[0055] In certain embodiments, the first consecutive dosing period comprises administering a once- daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once-daily dose is from 2.5 mg to 30 mg of AZD5004, or a pharmaceutically acceptable salt thereof, and the target dosing regimen comprises administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is from 50 mg to 150 mg of AZD5004, or a pharmaceutically acceptable salt thereof.

[0056] In certain embodiments, the escalating dosing regimen comprises at least three consecutive dosing periods, at least four consecutive dosing periods, at least five consecutive dosing periods, at least six consecutive dosing periods, or at least seven consecutive dosing periods.

[0057] In certain embodiments, the escalating dosing regimen comprises two consecutive dosing periods. In certain embodiments, the escalating dosing regimen comprises three consecutive dosing periods. In certain embodiments, the escalating dosing regimen comprises four consecutive dosing periods. In certain embodiments, the escalating dosing regimen comprises five consecutive dosing periods. In certain embodiments, the escalating dosing regimen comprises six consecutive dosing periods. In certain embodiments, the escalating dosing regimen comprises seven consecutive dosing periods.

[0058] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising six consecutive escalating dosing periods followed by a target dosing regimen.

[0059] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 1.25 to 2.5 times the fourth once-daily dose, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 1 to 4 weeks, wherein the sixth once-daily dose is 1.25 to 2.5 times the fifth once-daily dose, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the sixth once-daily dose.

[0060] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 1.25 to 2.5 times the fourth once-daily dose, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 2 weeks, wherein the sixth once-daily dose is 1.25 to 2.5 times the fifth once-daily dose, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the sixth once-daily dose.

[0061] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 1.25 to 2.5 times the fourth once-daily dose, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 1.25 to 2.5 times the fifth once-daily dose, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the sixth once-daily dose.

[0062] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 7.5 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 15 mg to 100 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 1 to 4 weeks, wherein the sixth once-daily dose is 25 mg to 125 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 to 150 mg.

[0063] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 7.5 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 15 mg to 100 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 2 weeks, wherein the sixth once-daily dose is 25 mg to 125 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 to 150 mg.

[0064] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from

[0065] 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 7.5 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 15 mg to 100 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 25 mg to 125 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 to 150 mg.

[0066] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is

[0067] 2.5 mg, 5 mg, or 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg, 15 mg, or 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 10 mg, 20 mg, or 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 15 mg, 25 mg, 40 mg, or 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 25 mg, 40 mg, 75 mg, or 100 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 1 to 4 weeks, wherein the sixth once-daily dose is 35 mg, 50 mg, 75 mg, or 100 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg.

[0068] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 2.5 mg, 5 mg, or 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg, 15 mg, or 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 10 mg, 20 mg, or 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 15 mg, 25 mg, 40 mg, or 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 25 mg, 40 mg, 75 mg, or 100 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 2 weeks, wherein the sixth once-daily dose is 35 mg, 50 mg, 75 mg, or 100 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg.

[0069] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 2.5 mg, 5 mg, or 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 5 mg, 15 mg, or 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 10 mg, 20 mg, or 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 15 mg, 25 mg, 40 mg, or 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 25 mg, 40 mg, 75 mg, or 100 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 35 mg, 50 mg, 75 mg, or 100 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg. In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg to 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 20 mg to 35 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 35 mg to 50 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 45 mg to 60 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 60 mg to 80 mg.

[0070] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 35 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 45 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 60 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 mg.

[0071] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 30 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 40 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 55 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 mg.

[0072] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 30 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 40 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 50 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 65 mg.

[0073] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 35 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 45 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 55 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 65 mg.

[0074] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is 2.5 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 10 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 15 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 25 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 1 to 4 weeks, wherein the sixth once-daily dose is 35 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg.

[0075] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 2.5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 10 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 15 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 25 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 2 weeks, wherein the sixth once-daily dose is 35 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg.

[0076] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 2.5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 5 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 10 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 15 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 25 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 35 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg.

[0077] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 75 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 1 to 4 weeks, wherein the sixth once-daily dose is 100 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 150 mg.

[0078] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 75 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 2 weeks, wherein the sixth once-daily dose is 100 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 150 mg.

[0079] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 75 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 100 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 150 mg.

[0080] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising five consecutive escalating dosing periods followed by a target dosing regimen.

[0081] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 1.25 to 2.5 times the fourth once-daily dose, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the fifth once-daily dose.

[0082] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 1.25 to 2.5 times the fourth once-daily dose, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the fifth once-daily dose.

[0083] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 1.25 to 2.5 times the fourth once-daily dose, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the fifth once-daily dose.

[0084] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 7.5 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 15 mg to 100 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 150 mg.

[0085] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 7.5 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 15 mg to 100 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 150 mg,

[0086] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from

[0087] 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 7.5 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 15 mg to 100 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 150 mg.

[0088] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 10 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 15 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 25 mg to 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 40 mg to 100 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 to 150 mg.

[0089] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg to 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 7.5 mg to 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 10 mg to 50 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 15 mg to 75 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg. In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is 2.5 mg, 5 mg, or 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg, 15 mg, or 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 10 mg, 20 mg, or 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 15 mg, 25 mg, 40 mg, or 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 25 mg, 40 mg, 75 mg, or 100 mg, f) after the fifth dosing period, wherein the target once-daily dose is 35 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg.

[0090] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 2.5 mg, 5 mg, or 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg, 15 mg, or 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 10 mg, 20 mg, or 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 15 mg, 25 mg, 40 mg, or 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 25 mg, 40 mg, 75 mg, or 100 mg, f) after the fifth dosing period administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg.

[0091] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 2.5 mg, 5 mg, or 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 5 mg, 15 mg, or 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 10 mg, 20 mg, or 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 15 mg, 25 mg, 40 mg, or 75 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 25 mg, 40 mg, 75 mg, or 100 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 35 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg.

[0092] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg to 30 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 20 mg to 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 35 mg to 55 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 45 mg to 75 mg. In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 55 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 mg.

[0093] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 30 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 50 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 65 mg.

[0094] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 35 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 50 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 65 mg.

[0095] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 35 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 45 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 65 mg.

[0096] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 30 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 45 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 65 mg.

[0097] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 25 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 35 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg.

[0098] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 20 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 35 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 45 mg.

[0099] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 25 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 35 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 45 mg.

[0100] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 1 to 4 weeks, wherein the fifth once-daily dose is 75 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 100 mg.

[0101] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 75 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 100 mg.

[0102] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 75 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 100 mg.

[0103] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising four consecutive escalating dosing periods followed by a target dosing regimen. a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the fourth once-daily dose.

[0104] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the fourth once-daily dose.

[0105] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 1.25 to 2.5 times the third once-daily dose, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the fourth once-daily dose.

[0106] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg to 35 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 7.5 mg to 75 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 10 mg to 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 150 mg.

[0107] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg to 35 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 7.5 mg to 75 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 10 mg to 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 150 mg.

[0108] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 2.5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 5 mg to 35 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 7.5 mg to 75 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 10 mg to 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 150 mg.

[0109] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg to 35 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 30 mg to 50 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 40 mg to 75 mg.

[0110] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 30 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 50 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 mg.

[0111] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 30 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 45 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 65 mg.

[0112] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 35 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg.

[0113] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 30 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 45 mg.

[0114] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 35 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 45 mg.

[0115] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 15 mg to 30 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 30 mg to 50 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 50 mg to 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 to 150 mg.

[0116] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 15 mg to 30 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 30 mg to 50 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 50 mg to 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 to 150 mg.

[0117] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from

[0118] 5 mg to 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 15 mg to 30 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 30 mg to 50 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 50 mg to 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 to 150 mg. In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 7.5 mg to 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg.

[0119] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 7.5 mg to 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg.

[0120] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 2.5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 5 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 7.5 mg to 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 10 mg to 75 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg. In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is

[0121] 5 mg, 10 mg, or 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 10 mg, 15 mg, 20 mg, or 25 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 15 mg, 25 mg, 40 mg, or 50 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 25 mg, 50 mg, 75 mg, or 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg, 75 mg, 100 mg, or 125 mg.

[0122] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 5 mg, 10 mg, or 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 10 mg, 15 mg, 20 mg, or 25 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 15 mg, 25 mg, 40 mg, or 50 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 25 mg, 50 mg, 75 mg, or 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg, 75 mg, 100 mg, or 125 mg.

[0123] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, 10 mg, or 15 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, 15 mg, 20 mg, or 25 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg, 25 mg, 40 mg, or 50 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 25 mg, 50 mg, 75 mg, or 100 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 mg, 75 mg, 100 mg, or 125 mg.

[0124] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 1 to 4 weeks, wherein the fourth once-daily dose is 75 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 100 mg.

[0125] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 75 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 100 mg.

[0126] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 40 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 75 mg, e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 100 mg.

[0127] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the third once-daily dose.

[0128] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the third once-daily dose.

[0129] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 1.25 to 2.5 times the second once-daily dose, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the third once-daily dose.

[0130] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 5 mg to 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 7.5 mg to 40 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 10 mg to 75 mg, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg. In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 5 mg to 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 7.5 mg to 40 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 10 mg to 75 mg, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg.

[0131] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 5 mg to 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 7.5 mg to 40 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 10 mg to 75 mg, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg.

[0132] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 15 mg to 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 20 mg to 50 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 1 to 4 weeks, wherein the third once-daily dose is 35 mg to 100 mg, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 to 150 mg.

[0133] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 15 mg to 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 20 mg to 50 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 35 mg to 100 mg, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 to 150 mg.

[0134] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from 15 mg to 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 20 mg to 50 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 35 mg to 100 mg, d) after the third dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 50 to 150 mg.

[0135] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 2.5 mg to 30 mg b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to

[0136] 2.5 times the second once-daily dose.

[0137] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from

[0138] 2.5 mg to 30 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to

[0139] 2.5 times the second once-daily dose.

[0140] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from

[0141] 2.5 mg to 30 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 1.25 to 2.5 times the first once-daily dose, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 1.25 to 2.5 times the second once-daily dose.

[0142] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is from 5 mg to 20 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 10 mg to 50 mg, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg.

[0143] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is from 5 mg to 20 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 10 mg to 50 mg, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 to 100 mg.

[0144] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is from

[0145] 5 mg to 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg to 50 mg, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 mg to 100 mg,

[0146] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 1 to 4 weeks, wherein the first once-daily dose is

[0147] 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 1 to 4 weeks, wherein the second once-daily dose is 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 75 mg, or 100 mg.

[0148] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 75 mg, or 100 mg.

[0149] In certain embodiments disclosed herein, the method of treating T2DM comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg, c) after the second dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 75 mg, or 100 mg.

[0150] Some embodiments disclosed herein provide a method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising administering a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising an escalating dosing regimen, where in the once-daily dose is increased every 1 to 4 weeks until a target dose is reached, and a target dosing regimen, wherein the target dose is administered once-daily.

[0151] In certain embodiments disclosed herein, the escalating dosing regimen (EDR) is selected from a EDR described in Tables A-G, wherein the last dose in the EDR is the target dose. Table A: Two-week dose escalation with a 2.5 mg starting dose

[0152] Table Bl: Two-week dose escalation with a 5 mg starting dose

[0153] Table B2: Two-week dose escalation with a 5 mg starting dose

[0154]

[0155] Table Cl: Four-week dose escalation with a 5 mg starting dose

[0156]

[0157] Table C2: Four-week dose escalation with a 5 mg starting dos

[0158] Table D: Four-week dose escalation with a 10 mg starting dose

[0159]

[0160] Table E: Weekly dose escalation with a 2.5 mg starting dose Table F: 4-week dose escalation schedule with a starting dose of 5-10 mg Table G: 2-week dose escalation schedule with a starting dose of 2.5 to 5 mg

[0161] Table H: 2-week dose escalation schedule with a starting dose of 5-10 mg

[0162] Certain embodiments disclosed herein are directed to AZD5004, or a pharmaceutically acceptable salt thereof, for use in the treatment of type 2 diabetes mellitus (T2DM), or any of the indications or conditions disclosed herein, wherein AZD5004 is administered orally once daily according to any of the dosing regimens described herein. In certain embodiments, the dosing regimen comprises an escalating dosing regimen followed by a target dosing regimen. In certain embodiments, the escalating dosing regimen comprises at least three consecutive dosing periods, at least four consecutive dosing periods, at least five consecutive dosing periods, at least six consecutive dosing periods, or at least seven consecutive dosing periods. Certain embodiments disclosed herein are directed to the use of AZD5004, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of type 2 diabetes mellitus (T2DM), wherein the medicament is for oral, once-daily administration according to any of the dosing regimens described herein. In certain embodiments, the dosing regimen comprises an escalating dosing regimen followed by a target dosing regimen. In certain embodiments, the escalating dosing regimen comprises at least three consecutive dosing periods, at least four consecutive dosing periods, at least five consecutive dosing periods, at least six consecutive dosing periods, or at least seven consecutive dosing periods. Indications

[0163] Improving Glycemic Control

[0164] Some embodiments disclosed herein provide a method of improving glycemic control in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of improving glycemic control in a subject with type 2 diabetes mellitus (T2DM) comprising administering AZD5004, or a pharmaceutically acceptable salt thereof.

[0165] Reducing the risk of MACE

[0166] Some embodiments disclosed herein provide a method of reducing the risk of major adverse cardiovascular events (MACE) in a subject in need there of comprising administering AZD5004, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of reducing the risk of major adverse cardiovascular events in a subject with type 2 diabetes mellitus (T2DM) comprising administering AZD5004, or a pharmaceutically acceptable salt thereof.

[0167] Improving outcomes in subjects with CKD

[0168] Some embodiments disclosed herein provide a method of reducing the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, or hospitalization for heart failure in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject has chronic kidney disease (CKD). In other embodiments, the subject has chronic kidney disease at risk of progression. In yet other embodiments, the subject has T2DM and chronic kidney disease. In other embodiments, the subject has T2DM and chronic kidney disease at risk of progression. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once- daily dose according to a dosing schedule described herein. Type 2 Diabetes Mellitus

[0169] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof. In further embodiments, the subject is in need of glycemic control.

[0170] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 6.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 7.0%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 7.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 8.0%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 8.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 9.0%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 9.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 10.0%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 10.5%. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0171] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 6.5% and less than or equal to 10.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 7.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 7.5% and less than or equal to 10.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 8.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 8.5% and less than or equal to 10.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 9.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 9.5% and less than or equal to 10.5%. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0172] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 6.5% and less than or equal to 9.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 7.0% and less than or equal to 9.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 7.5% and less than or equal to 9.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 8.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 8.5% and less than or equal to 10.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 9.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 9.5% and less than or equal to 10.5%. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0173] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 0.5%, at least 1.0%, at least 1.2%, at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0%. In further embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still further embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once- daily dose according to a dosing schedule described herein.

[0174] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 4, 6, 8, 10, 12, or 14 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0175] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 16 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0176] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 18, 20, 22, or 24 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein. Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 26 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0177] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 4, 6, 8, 10, 12, or 14 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0178] Some embodiments disclosed herein provide a method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, according to a dosing schedule described herein, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof at the target once-daily dose. Lowering HbA 1c

[0179] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 6.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 7.0%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 7.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 8.0%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 8.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 9.0%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 9.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 10.0%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 10.5%. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0180] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 5.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 5.7%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 6.0%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 6.2%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 6.4%. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0181] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 6.5% and less than or equal to 10.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 7.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 7.5% and less than or equal to 10.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 8.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 8.5% and less than or equal to 10.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 9.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 9.5% and less than or equal to 10.5%. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0182] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 6.5% and less than or equal to 9.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 7.0% and less than or equal to 9.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 7.5% and less than or equal to 9.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 8.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 8.5% and less than or equal to 10.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 9.0% and less than or equal to 10.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 9.5% and less than or equal to 10.5%. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0183] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 5.5% and less than or equal to 6.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 5.7% and less than or equal to 6.5%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 6.0% and less than or equal to 6.5%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 6.2% and less than or equal to 6.5%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 6.4% and less than or equal to 6.5%. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once- daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0184] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has an initial HbAlc equal to or greater than 5.5% and less than or equal to 7.0%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 5.7% and less than or equal to 7.0%. In a further embodiment, the subject has an initial HbAlc equal to or greater than 6.0% and less than or equal to 7.0%. In a still further embodiment, the subject has an initial HbAlc equal to or greater than 6.2% and less than or equal to 7.0%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 6.4% and less than or equal to 7.0%. In a yet further embodiment, the subject has an initial HbAlc equal to or greater than 6.5% and less than or equal to 7.0%. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0185] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 0.5%, at least 1.0%, at least 1.2%, at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0%. In other embodiments, the subject has T2DM. In further embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still further embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0186] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 4, 6, 8, 10, 12, or 14 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0187] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 16 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0188] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 18, 20, 22, or 24 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0189] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 26 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0190] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 4, 6, 8, 10, 12, or 14 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0191] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, without a period of dose escalation, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0192] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, according to an escalating dosing schedule described herein, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof at the target once-daily dose. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once- daily dose according to a dosing schedule described herein.

[0193] Some embodiments disclosed herein provide a method of lowering HbAlc in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, according to a dosing schedule described herein, wherein the subject’s initial HbAlc is lowered by at least 1.5%, at least 1.7%, at least 2.0%, at least 2.2%, at least 2.5%, at least 2.7%, at least 3.0%, at least 3.2%, at least 3.5%, at least 3.7%, at least 4.0%, at least 4.2%, at least 4.5%, at least 5.7%, or at least 6.0% after 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof at the target once-daily dose. In other embodiments, the subject has T2DM. In yet other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In still other embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0194] Weight loss and chronic weight management

[0195] Some embodiments disclosed herein provide a method for chronic weight management in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has T2DM. In certain embodiments, the subject has an initial BMI greater than 25 kg / m2. In further embodiments, the subject has an initial BMI of greater than 26 kg / m2. In yet further embodiments, the subject has an initial BMI of greater than 27 kg / m2. In still further embodiments, the subject has an initial BMI of greater than 28 kg / m2. In yet still further embodiments, the subject has an initial BMI of greater than 29 kg / m2. In even further embodiments, the subject has an initial BMI of greater than 30 kg / m2. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0196] Some embodiments disclosed herein provide a method for chronic weight management in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject has T2DM and an initial BMI greater than 25 kg / m2, 26 kg / m2, 27 kg / m2, 28 kg / m2, 29 kg / m2, or 30 kg / m2. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0197] Some embodiments disclosed herein provide a method of lowering initial BMI in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial BMI is lowered by at least 0.5 kg / m2, 1 kg / m2, 1.5 kg / m2, 2 kg / m2, 2.5 kg / m2, 3 kg / m2, 3.5 kg / m2, 4 kg / m2, 4.5 kg / m2, 5 kg / m2, 5.5 kg / m2, 6 kg / m2, 7.5 kg / m2, 8 kg / m2, 9 kg / m2, 10 kg / m2, 12 kg / m2, or 15 kg / m2. In certain embodiments, the subject’s initial MI is lowered by at least 0.5 kg / m2, 1 kg / m2, 1.5 kg / m2, 2 kg / m2, 2.5 kg / m2, 3 kg / m2, 3.5 kg / m2, 4 kg / m2, 4.5 kg / m2, 5 kg / m2, 5.5 kg / m2, 6 kg / m2, 7.5 kg / m2, 8 kg / m2, 9 kg / m2, 10 kg / m2, 12 kg / m2, or 15 kg / m2, after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof at the target once-daily dose. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein. Some embodiments disclosed herein provide a method of lowering initial body weight in a subject in need thereof comprising administering AZD5004, or a pharmaceutically acceptable salt thereof, wherein the subject’s initial body weight is lowered by at a least 2%, at least 5%, at least 7%, at least 10%, at least 12%, at least 15%, at least 17%, at least 20%, at least 22%, at least 25%, or at least 30%' In certain embodiments, the subject’s initial body weight is lowered by at a least 2%, at least 5%, at least7%, at least 10%, at least 12%, at least 15%, at least 17%, at least 20%, at least 22%, at least 25%, or at least 30%, after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of administering AZD5004, or a pharmaceutically acceptable salt thereof at the target once-daily dose. In any of the above embodiments, the subject has T2DM. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose. In any of the above embodiments AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein.

[0198] Concurrent Administration with Statins

[0199] Some embodiments disclosed herein provide a method of administering a statin and AZD5004, or a pharmaceutically acceptable salt thereof. Certain embodiments disclosed herein provide a method of administering a statin and AZD5004, or a pharmaceutically acceptable salt thereof, wherein AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein, and the statin is administered at the lowest recommended dose. In certain embodiments, the statin is selected from rosuvastatin, atorvastatin, simvastatin, and pravastatin. Certain embodiments disclosed herein provide a method of administering rosuvastatin and AZD5004, or a pharmaceutically acceptable salt thereof, wherein AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein, and rosuvastatin is administered at 10 mg a day or less. Certain embodiments disclosed herein provide a method of administering rosuvastatin and AZD5004, or a pharmaceutically acceptable salt thereof, wherein AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein, and rosuvastatin is administered at 5 mg a day or less. Certain embodiments disclosed herein provide a method of administering rosuvastatin and AZD5004, or a pharmaceutically acceptable salt thereof, wherein AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein, and rosuvastatin is administered at 2.5 mg a day or less. Certain embodiments disclosed herein provide a method of administering atorvastatin and AZD5004, or a pharmaceutically acceptable salt thereof, wherein AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein, and atorvastatin is administered at 20 mg a day or less. Certain embodiments disclosed herein provide a method of administering simvastatin and AZD5004, or a pharmaceutically acceptable salt thereof, wherein AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein, and simvastatin is administered at 20 mg a day or less. Certain embodiments disclosed herein provide a method of administering pravastatin and AZD5004, or a pharmaceutically acceptable salt thereof, wherein AZD5004, or a pharmaceutically acceptable salt thereof, is administered as a once-daily dose according to a dosing schedule described herein, and pravastatin is administered at 20 mg a day or less.

[0200] EXAMPLES

[0201] Example 1: In vitro assessment of potency and efficacy of AZD5004

[0202] Radioligand binding assay

[0203] Binding to the human GLP-1R was assessed in a radioligand binding assay as follows. Membranes were prepared according to standard methods from CHO-K1 cells (ATCC® CCL- 61™) transfected and selected to stably express the human GLP-1R (Uniprot #P43220) and protein concentration was determined using Bradford method. Multiscreen HTS+ HiFlow FB filter plate (Merck) was pre-soaked with 0.3% PEI (Sigma) to reduce unspecific binding and washed with assay buffer (HBSS, 20 mM Hepes, pH 7.4 + 0.1% BSA) before the start of experiment.

[0204] Membranes (1.6pg / well) diluted in assay buffer were added to a 96 well plate (Corning#3600) containing a 10-point serial dilution of AZD5004 in DMSO. The radioligand125I-GLP-1(7-36)NH2 (Revvity #NEX308), diluted in assay buffer was added to a final concentration of 75pM. The plate was sealed and incubated on a shaker for 2 hours 15 minutes at room temperature. Free radioligand was separated from bound by filtration using Bravo with a vacuum manifold (Agilent). The filter plate was washed with ice-cold wash buffer (25 mM HEPES, 1.5 mM CaCl2, 1 mM MgCh, 100 mM NaCl, 0.1% BSA, 0.05% Tween20, pH 7.4) and dried at 50°C for 1 hour. Ultima Gold™ XR Scintillation fluid (Revvity) was added, plates were sealed and after 10 hours at room temperature radioactivity was measured using Microbeta2 2450 Micro Plate Counter (Revvity). AZD5004 binds to the human GLP-1R with a potency of 2.4 nM (Figure 1A). cAMP assay for human GLP-1R and cynomolgus GLP-1R cAMP production upon activation of the human and cynomolgus GLP-1R was measured using CisBio’s HTRF cAMP Gs Dynamic range kit (#62AM4PEC) in different cell systems overexpressing the respective receptor.

[0205] CHO-K1 cells overexpressing the human GLP-1R, as described for the radioligand binding assay, were dispensed (800 cells / well) in assay buffer (HBSS, 20mM Hepes pH 7.4, 0.1% Bovine Serum Albumin) into 348-well low volume plates (Greiner, 784076) containing a 10- point serial dilution of AZD5004 in assay buffer with IB MX (final assay concentration 0.5mM). Plates were incubated at room temperature for 20 minutes before addition of cAMP-d2 and anti- cAMP cryptate in conjugate and cell lysis buffer. Following this, the assay plates were incubated at room temperature for one hour before reading fluorescence on a PHERAstar (BMG LABTECH) with Aex=340 nm, Aem=665 and 615 nm. A cAMP standard curve was employed in each experiment to convert fluorescence data to cAMP concentrations. AZD5004 has an Emax of 30 % and ECso estimate of 45 nM in the human GLP-1R cAMP assay (Figure IB).

[0206] Chinese hamster ovary (CHO) cells expressing cynomolgus GLP-1R (1000 cells / well) were dispensed into a 384-well plate containing an 11 -point serial dilution of AZD5004 in assay buffer. After a 30-minute compound incubation, cAMP levels were measured using a commercial cAMP dynamic GS Homogeneous Time Resolved Fluorescence (HTRF) kit (cAMP dynamic 2 HTRF kit Cat # 62AM4PEJ, Cisbio, Codolet, France) according to the manufacturer's instructions. The data was transformed to % Delta F as per the manufacturer’s instructions before determining the ECso. AZD5004 exhibited a robust dose-dependent effect on potentiating cAMP secretion in a cell line overexpressing the cynomolgus GLP-1R (ECso 7.7 nM; Figure 2A). fi-arrestin-2 recruitment assay

[0207] P-arrestin-2 recruitment after stimulation of the human GLP-1R was investigated using a commercially available assay from Eurofins (formerly DiscoverX, USA). CHO KI hGLP-lR P- arrestin-2 cells (Eurofins #93-0300C2) in assay buffer (Ham’s F12+ 1% FBS) was plated in 384- well assay plates (Greiner #781080) at a density of 3000 cells / well and incubated at 37°C in 5% CO2 overnight. A 10-point serial dilution of compounds in assay buffer was added to the cells using Bravo (Agilent Technologies), followed by a 90 minute incubation at 37°C and 5% CO2. The PathHunter detection reagent was prepared according to the manufacturer’s instructions and added to the cells. Plates were incubated dark for 60 minutes at room temperature before luminescence was measured on an Envision (Revvity).

[0208] In contrast to GLP-1(7-36)NH2, which is a full agonist, AZD5004 does not demonstrate detectable P-arrestin-2 recruitment (Figure 1C).

[0209] GLP-1R internalization assay

[0210] Human GLP-1R internalization was examined using an imaging assay in U2OS cells overexpressing Fluorogen Activating Protein P (FAPP)-tagged human GLP-1R (SpectraGenetics). In short, 3000 cells / well in cell culture medium (DMEM+ 10%FBS + 0.4 mg / ml Geneticin) were added to 384w Cell Carrier plates (PerkinElmer #6057302) and incubated overnight at 37°C and 5% CO2. On the day of the experiment, cell culture media was removed using a BlueWasher (BlueCat Bio) followed by addition of Hoechst (Life Technologies #H3570), beta-red dye (Spectragenetics, pRED-np-010) and serially diluted compound in PBS + 0.1% BSA. Final concentration of the beta-red dye was 56 nM and Hoechst was diluted 1 : 10000. Following a 30-minute incubation at 37°C, Paraformaldehyde (PF A) was added in a ventilated hood to a final concentration of 4%. After 20 minutes PFA was removed and the plate was washed with PBS in the BlueWasher (Gentle spin wash), leaving 50 pl PBS post wash. The plate was imaged using CellVoyager 8000 (Yokogawa Electric) with a 20x water immersion objective. A 405nm laser with a bandpass 445 / 45 filter was used to acquire the Hoechst images and a 640nm laser with a bandpass 676 / 29 filter was used to acquire the P -red dye labeled FAPpi-hGLPIR. Internalization was quantified using the Columbus Image analysis software (PerkinElmer / Revvity). In short, nuclei were segmented using the DAPI channel (BP445 / 45) and the cytoplasm was defined using the same channel by looking at the weak background fluorescence. Fluorescence intensity at 676 / 29 nm was used to quantify internalization of the P- red dye in the cytoplasm. The mean fluorescence intensity per cell was calculated and the well median was imported into Genedata Screener (Genedata AG) for curve fitting analysis. The potency (ICso or ECso) of AZD5004 was assessed in different cell systems (Figure 1 and Table 1). Similarly, GLP- 1 (7-36)NH2 internalizes the GLP-1R, while GLP-1R internalization is not observed in response to AZD5004 (Figure ID).

[0211] Table 1. Summary of preclinical potency values in vitro and in vivo Calculations based on 3-4 separate test occasions except for the cAMP assay in HEK293 where n= 51. Emax = The fitted maximum activity level, efficacy, at infinite concentration of test compound. N= 3-4 / dose group for the NHP ivGTT experiments.aEffect (%) was <10% across all tested concentrations, up to 12pM for P-arrestin 2 and 10 pM for internalization.bData refer to Exendin-4. Abbreviations: GSIS, glucose-stimulated insulin secretion; IC50, half-maximal inhibitory concentration; NA, not applicable; NHP, non-human primate; SD, standard deviation.

[0212] Glucose-stimulated insulin secretion (GSIS)

[0213] Glucose-stimulated insulin secretion (GSIS) experiments were conducted in EndoC-|3H5 cells as described in Bianchi et al.28Human-derived P EndoC-PH5 cells were seeded at 75,000 cells per well in ULTipi® Complete culture medium. Cells were cultured for 6 days, and then the media was changed to ULTI-ST® on day 7. On day 8, Exendin-4 and AZD5004 were manually added in assay buffer plus 11 mM glucose (100 pL per well) to cell plates and incubated at 37°C for 40 minutes. At the end of the incubation, the cell supernatant was collected, and insulin concentration was measured using the MSD Human Insulin Kit (K151BZC).

[0214] In EndoC-PH5 cells, AZD5004 exhibits a dose-dependent effect on potentiating insulin secretion at 11 mM glucose (ECso = 5.6).

[0215] The in vitro assays included the endogenous peptide GLP-1(7-36)NH2, exendin-4, or the small molecule danuglipron as positive controls.

[0216] Example 2: Pharmacokinetics and pharmacodynamics in Non-Human Primates (NHPs)

[0217] The PK study was performed at WuXi AppTec (Shanghai) Co., Ltd (study number: 414519- 2020111001-CPK). AZD5004 (0.5 mg / kg, in 10% PEG400 / 10% PG / 80% 100 mM Glycine- NaOH pH 8-9) was administered as a single intravenous bolus to male cynomolgus monkeys (Macaca fascicularis; n=3). Repeated blood samples were collected from a peripheral vein at 0.08, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose. Following protein precipitation of the plasma samples with acetonitrile, the concentration of AZD5004 was quantified by LC-MS / MS. PK parameters were estimated by using non compartmental analysis in MATLAB® (Version 2021b).

[0218] Intravenous glucose tolerance tests (IVGTTs) were performed in 22 male cynomolgus monkeys, with a mean age of 17.7 years (Standard Deviation (SD 3.4)), and a mean weight of 11.4 kg (SD 1.8), and a glucose disposal rate Kg below 2%.. Following a training and selection period, three IVGTT rounds separated by 2 weeks were performed: baseline, where all animals were treated with vehicle (30% w / w Kleptose + 3% w / w DMSO), followed by two rounds with compound dosing. Before each IVGTT with compound treatment, the animals were randomized to new treatment groups (n = 3-4 / group). In total, six different doses of AZD5004 were evaluated: 5, 15, 33, 100, 160 and 330 pg / kg all administered intravenous just before the glucose bolus (0.5 g / kg). The animals were overnight fasted and anesthetized with ketamine during the IVGTT. Repeated blood samples were collected over 60 minutes for analysis of glucose (Roche C311 / C501 biochemical analyzer), insulin (Cobas e411 Immunology analyzer) and compound levels (mass spectrometry).

[0219] PK studies in lean NHPs showed that after intravenous dosing, AZD5004 had a mean half-life of 1.72 hours (SD 0.405), mean plasma clearance of 14.4 mL / min / kg (SD 1.32) and mean volume of distribution of 0.651 L / kg (SD 0.138) (Figure 2B). Together, with the cAMP cynomolgus GLP-1R data, these data were used to set doses for the following PD assessment of AZD5004 in obese NHP.

[0220] The effect of AZD5004 in the IVGTTs were compared to the baseline (vehicle) round where the model fitted data for insulin and glucose area under the concentration-time curve (AUC) and Kg (inclusion criteria included Kg below 2%) were: insulin AUC 22898 ± 5876 pU / mL*min; glucose AUC 13732 ± 349 mg / dL*min and Kg 1.30 ± 0.06%. AZD5004 at the highest four doses (33, 100, 160 and 330 pg / kg) showed a robust insulin response (insulin AUC change from baseline: 29998 ± 9221, 45067 ± 9406, 44721 ± 8586 and 37209 ± 10553 pU / mL*min, respectively, adjusted P < 0.05). (Figure 2C) exemplifies the potentiation of insulin secretion with the 33 pmol / kg dose compared to vehicle. The glucose disposal rate (Kg) was increased at the 4 highest doses in line with the increased insulin AUC (Kg % change from baseline: 0.31 ± 0.03, 0.52 ± 0.04, 0.52 ± 0.03 and 0.45 ± 0.04% corresponding to 33, 100, 160 and 330 pg / kg, respectively, adjusted P < 0.0001). Glucose AUC was not significantly different compared with baseline (data not shown). Using the insulin AUC dose-response data and corresponding free average AZD5004 plasma exposures a PK / PD plot was made (Figure 2D), and the in vivo potency was estimated to ECso = 0.022 nM. Statistical analysis

[0221] The study was powered to detect a significant change in insulin area under the curve (AUC) compared to vehicle following baseline correction. AZD5004 in vivo potency (EC50) was estimated by fitting a direct response model to the insulin AUC response and total exposure corrected for AZD5004 plasma protein binding. Model fitting was performed by using curve fit statistical toolbox in MATLAB® (Version 2021b).

[0222] The insulin and glucose responses, along with the percentage of glucose clearance, were each analyzed using linear mixed effects models (implemented via the nlme package in R), treating multiple measurements from each animal as a random effect. The effects of treatment, bodyweight at baseline, time point, fasted insulin / glucose measure for individual IVGTT rounds, the interaction between fasted insulin / glucose for individual IVGTT rounds and treatment group and the interaction between timepoint and treatment were modelled as fixed effects. The model dedicated to the percentage of glucose clearance also included fasted glucose measure for each individual IVGTT round, treatment, bodyweight at baseline, the interaction between bodyweight at baseline and fasted glucose measure for individual IVGTT rounds, and the interaction between fasted glucose measure for individual IVGTT rounds and treatment as fixed effects. In all models, fasting insulin and glucose levels were recorded at each IVGTT session, and an autocorrelation structure of the first order was applied.

[0223] For the insulin and glucose response models, estimated marginal means were computed for each timepoint across treatment groups or baseline, whereas for the percentage glucose clearance model, these means were calculated for each treatment group. These calculations were performed using the Satterthwaite method for estimating degrees of freedom, as facilitated by the emmeans package in R. Custom contrasts based on the trapezoidal rule were employed to derive the area under the curve (AUC) for insulin or glucose for each group, compared against the baseline. Additionally, a Bonferroni correction was applied to adjust for the impact of multiple testing.

[0224] Statistical analysis of bodyweight changes for NHP

[0225] Percent change from baseline in body weight was analyzed using a linear mixed effects model with repeated measurements adjusting for fixed effects of baseline weight, treatment, sex, day, sex by day interaction, sex by treatment interaction, and treatment by day interaction as fixed factors. An auto regressive (1) covariance structure was used together with the Satterthwaite method for estimating degrees of freedom. Results are presented graphically as LS mean difference in percent change from baseline in body weight versus control over time including a 95% confidence interval. Analysis, using Ime (from the nlme package) and emmeans (from the emmeans package), and graphs were performed in R Statistical Software (v4.1.0; R Core Team 2021).

[0226] Chronic NHP toxicology study

[0227] Effects of AZD5004 on food consumption and body weight were assessed in healthy cynomolgus monkeys as part of a 9-month chronic toxicity study. Groups of six male and six female monkeys (two per group / sex for recovery assessment) received daily oral doses of AZD5004 at dose levels of 10, 30 or 50 mg / kg / day for 39 weeks. AZD5004 was given as an amorphous solid dispersion with Kollidon VA64 and TPGS 1000 (10: 1) formulated in 0.25% (v / v) Tween80 in purified water at a volume of 5 mL / kg / day. The control group was administered control article formulation matching the high dose Kollidon VA64 and TPGS 1000 contents.

[0228] To resemble the up-titration, or escalation, regimen of GLP-1R agonists in the clinical setting, a two-week titration (dose escalation) period was included. During these two weeks the control, AZD5004 low- and mid-dose groups were administered control article formulation or 10 mg / kg / day or 30 mg / kg / day of AZD5004. The AZD5004 high-dose group was first administered AZD5004 30 mg / kg / day for 14 consecutive days, then increased to 50 mg / kg / day through week 39. Food consumption was assessed by daily visual inspection for overall appetite and bodyweights were recorded weekly.

[0229] During the titration (dose escalation) period (days -14 to -1), slight mean body weight losses were seen in all AZD5004 groups except for the males at 10 mg / kg / day. On day -1, group means in the affected groups were decreased by 1.3% to 6.4% when compared with day -15 values. In the dosing phase, the AZD5004 group means of body weights were generally well maintained, while body weight increases were observed in the control groups. As a result, the percentage change in body weight gain over time showed a dose-dependent decrease in the treated groups (Figure 3). At the end of the study, in the 10, 30 and 50 mg / kg / day groups, the LS mean changes in body weight gain compared to control were decreased with 14.7%, 26.2% and 30.9% in males and 11.3%, 13.5% and 17.1% in females (Figure 3).

[0230] At the end of treatment, there were no test article-related changes in laboratory assessments, ECG, organ weights, gross or histopathology examinations at any dose level. Therefore, the no observed adverse effect level (NOAEL) of AZD5004 was 50 mg / kg / day in cynomolgus monkeys.

[0231] Example 3: Human MAD and SAD Studies

[0232] This was a phase I, multicenter, double-blind, randomized, placebo-controlled, first-inhuman study of AZD5004 in healthy volunteers and patients with T2DM. The primary objective was to assess safety and tolerability; secondary and exploratory objectives were to evaluate PK and PD parameters, respectively. No calculation of power or sample size were performed. Statistical analyses were performed using SAS® 8.2 or higher programming software (SAS Institute, Inc., Cary, NC) or R Statistical Software (v4.1.0; R Core Team 2021). Figure 4 shows the study design for the SAD and MAD studies.

[0233] In brief, the study was conducted at two sites in the USA in accordance with the principles of the Declaration of Helsinki, the International Conference of Harmonization Good Clinical Practice, and all applicable regulatory requirements, and was approved by an institutional review board. All participants provided written informed consent before participating and could withdraw at any time.

[0234] Safety analyses

[0235] The total number of adverse events, serious adverse events, and adverse events leading to withdrawal from the study and the corresponding frequency and incidence were calculated by study cohort using the safety analysis set. Adverse events were coded by MedDRA (version 23.0 or higher) terminology, classified by System Organ Class / Pref erred Terminology, and the frequency and incidence of adverse events were summarised according to System Organ Class and severity. Laboratory assessments, 12-lead electrocardiography (ECG) and physical examinations were regularly monitored in both studies. Statistical analysis ofPD markers

[0236] Baseline was defined as the last assessment prior to the first administration of study intervention. The analysis for change / percentage change from baseline was performed using a linear mixed effects model with repeated measurements, where appropriate, adjusting for fixed effects of baseline, treatment, timepoint and treatment by timepoint interaction. An auto regressive covariance structure was used together with the Kenward-Rogers method for estimating degrees of freedom. All participants that had at least one dose of IP was included in the analysis, with the extra constraint that they had no missing covariates. The analysis of PD markers in the MAD part of the study was performed by Cohort. No adjustments for multiplicity were performed.

[0237] AUCO-4 for glucose, insulin, C-peptide and glucagon from the MMTT in the MAD part were log- transformed before analysis, including the log-transform of the corresponding baseline as covariate. Results were back-transformed to represent percent change from baseline (Percent change from baseline = (exp(Change from baseline in log-transformed estimate) - 1) * 100).

[0238] The analysis of AUCO-2 for glucose and insulin from the OGTT in the SAD part was also performed on log-transformed data, but using an ANCOVA as there were only one pair of measurements, before and after dose, for each participant. Results were back-transformed in the same way as for the MMTT data.

[0239] Analysis was performed using proc mixed in SAS® v9 programming software (SAS Institute, Inc., Cary, NC) and graphs were produced in R Statistical Software (v4.1.0; R Core Team 2021).

[0240] SAD study

[0241] The SAD study was initiated and completed between April and December 2023. Two sequential cohorts, each having eight healthy adult participants aged 18-65 years, with body mass index (BMI) between 18.0 and 32.0 kg / m2, were randomized to receive AZD5004 or placebo in four ascending dose periods (Cohort Al : 1 mg, 4 mg, 10 mg, and 25 mg; Cohort A2: 50 mg, 100 mg, 200 mg, and 300 mg). The active versus placebo ratio was 6:2, and each participant received up to three doses of AZD5004 and one dose of placebo. A washout period of 14 days ensued before escalation to the next higher dose and participants were fasted for 10 hours prior to dosing, and 4 hours afterwards.

[0242] Safety

[0243] In the SAD study, 39 participants were screened, and 19 participants randomized (Cohort Al : 10 participants, including two replacements; Cohort A2: nine participants, including two replacements). A total of 16 participants (eight in each in cohort) completed the study. Baseline demographics were well-balanced between cohorts. AZD5004 was generally well tolerated and there were no reported serious adverse events nor deaths. There were two discontinuations due to oral candidiasis and COVID-19 infection. Gastrointestinal (GI) adverse events (AEs) were most frequently reported, and a dose-dependent increase in treatment-emergent adverse events (TEAEs) was observed. There were no clinically relevant abnormalities in laboratory assessments, 12-lead ECG recordings or vital signs.

[0244] Pharmacokinetics

[0245] Pharmacokinetic blood samples were collected pre-dose within 1 hour of dosing, and 0.25, 0.5, 1, 2, 4, 8, 12, 24 (Day 2) and 48 (Day 3) hours post-dose.- The non-compartmental analysis method by Phoenix™ WinNonlin® (version 8.0 or higher, Certara) were used for pharmacokinetic analyses.

[0246] Dose-dependent increases of plasma concentrations of AZD5004 were observed at doses above 25 mg (Figure 5). Across both cohorts, the geometric mean of Cmax increased from 1.97 ng / mL (geometric coefficient of variation [gCV] 62.3%, AZD5004 1 mg) to 1784.69 ng / mL (gCV 118.2%, AZD5004 300 mg). Median tmax ranged between 7.98 hours (range 4.00-11.97 hours, AZD5004 4 mg) and 12.08 hours (range 8.00-48.00 hours, AZD5004 300 mg). The median elimination half-life (ti / 2) of AZD5004 ranged between 10.66 hours (range 10.66-10.66 hours, AZD5004 100 mg) and 24.96 hours (range 22.12-26.56 hours, AZD5004 1 mg) (Table 2).

[0247] Table 2. Pharmacokinetic parameters

[0248] Abbreviations: AUCo-«>, area under the plasma concentration-time curve from time zero extrapolated to infinity; AUCo-iast, area under the plasma concentration-time curve from time zero to the last measurable nonzero concentration; CL / F, oral clearance; gCV%, geometric coefficient of variation; Cmax, maximum concentration; GM, geometric mean; MAD, multiple ascending dose; SAD, single ascending dose; ti / 2, elimination half-life time; tmax, time to maximum concentration.

[0249] Exploratory pharmacodynamics

[0250] The OGTT showed reductions in mean plasma glucose levels with AZD5004 4 mg or higher doses (Figure 6A). The percent least square (LS) mean of glucose AUC0-2 reductions ranged between -17.73% (95% CI -25.10, -9.65, AZD5004 4 mg) and -38.04% (-43.57, -31.74, AZD5004 300 mg). Concurrent reductions in plasma insulin levels were also observed (Figure 6B).

[0251] Pharmacodynamic analyses

[0252] The parameters used to assess the pharmacodynamics of AZD5004 include: area under the plasma concentration-time curve from time 0 to 2- and 4-hours post-dose (AUCO-2 or AUCO-4) for glucose, insulin, glucagon and C-peptide, change from baseline in FPG, mean daily glucose levels (MDG), fasting plasma insulin (FPI) levels, bodyweight and waist circumference. Data were analysed for each participant using Mixed-Meal Tolerance Test (MMTT), Oral Glucose Tolerance Test (OGTT), Homestoatic Model Assessment for Insulin Resistance (HOMO-IR) as appropriate.

[0253] Participants completed a baseline OGTT after fasting for 10 hours on Day -1, and blood samples were collected for plasma glucose and insulin testing immediately before (0 hour) and at 0.25, 0.5, 1.0, 1.5 and 2 hours post oral intake of 75 g glucose. Participants stayed in the fasted state and completed a post-dose OGTT 4 hours after dosing. The last blood sample for OGTT were collected 2 hours post oral glucose intake. MAD study

[0254] The MAD study was initiated and completed between April and December 2023. Four sequential cohorts, each with 12 adult participants adults aged 18-70 years, with BMI between 24.0 and 40.0 kg / m2, HbAic between 7.0 and 10.5%, and T2DM treated with metformin were randomized 9:3 to receive either AZD5004 (5 mg, 10 mg, 30 mg, or 50 mg) or placebo once daily for up to 28 days. The 50 mg cohort was up-titrated to receive AZD5004 10 mg on days 1- 7, 25 mg on days 8-14 and 50 mg on days 15-28. All participants were hospitalized from day -2 to 48 hours post last dose (day 30) and had the same fasting conditions as the SAD study.

[0255] In the MAD study, 188 participants were screened, and 52 participants were randomized (39 participants to AZD5004 treatment and 13 participants to placebo). A total of 48 participants (92.3%) completed the study. One participant in each AZD5004 treatment group and in placebo discontinued the study. Baseline demographics and characteristics were balanced between treatment groups and placebo. All participants had T2DM, 55.8% were male and 76.9% were White. Participants had a mean age of 56.2 years and a mean BMI of 31.73 kg / m2.

[0256] Safety

[0257] Multiple doses of AZD5004 were generally well tolerated. There were no reported serious adverse events nor deaths, and most AEs were mild, with GI AEs being most common. Two participants experienced TEAEs that led to study discontinuation: one with QTc prolongation in the AZD5004 30 mg cohort, which occurred on day 1, and one with asymptomatic and transiently elevated liver enzymes noted on pre-dose blood tests on day 7 at the 10 mg dose level in Cohort 4, which fell despite increasing exposure and resolved spontaneously. There were no other clinically treatment-emergent relevant changes in biochemical, urinalysis and hematological parameters. Mean increases in pulse rate were observed of up to +2.7 bpm (95% CI -2.4, +7.9; n = 9) at 50 mg versus -7.0 bpm (95% CI -16.0, 1.9; n = 3) in placebo participants in the same cohort. No clinically significant changes in systolic or diastolic blood pressure were observed. Pharmacokinetics and metabolism

[0258] Pharmacokinetic blood samples were collected pre-dose within 1 hour of dosing, and 0.25, 0.5, 1, 2, 4, 8, 12, 24 (Day 2) hours post-dose on Day 1, and pre-dose within 1 hour of dosing, and 0.25, 0.5, 1, 2, 4, 8, 12, 24 (Day 29) and 48 hours (Day 30) post-dose on Day 28, and at predose on Day 4, 7, 10, 14, 17, 21 and 24. The non-compartmental analysis method by Phoenix™ WinNonlin® (version 8.0 or higher, Certara) were used for pharmacokinetic analyses. Dosedependent increases in concentrations of AZD5004 were observed and PK parameters were consistent with findings in the SAD study (Table 2).

[0259] On metabolite profiling, plasma samples were collected at 0.5, 2, 8, and 24 hours after a 50 mg dose in 7 participants in the MAD study on Day 28. A plasma AUC pool (0 to 24 hours) (Hamilton et al., 1981, Hop et al., 1998) was generated for each participant. Following extraction of the pooled plasma samples with three volumes of acetonitrile, samples were mixed, centrifuged, and the supernatant analysed by LC-HRMS. Metabolites were detected by manual data mining of LC / MS spectra for expected biotransformation products of AZD5004. To screen for unexpected metabolites, software for automatic identification of metabolites (i.e. Mass- MetaSite, Molecular Discovery Ltd.) was applied. AZD5004 was the predominant drug-related component detected in human plasma at steady-state following 50 mg daily dosing, accounting for 92-97% of drug-related exposure (DRE). The major metabolite, accounting for 1-6% of DRE, was formed by mono-oxidation of AZD5004.

[0260] Pharmacodynamics

[0261] Mixed-meal tolerance tests (MMTTs) showed reductions in fasting glucose and glucose AUC levels across all treatment groups. On day 28, in the AZD5004 50 mg cohort, the LS mean change from baseline in fasting glucose levels was -76.6 mg / dL (95% CI -106.8, -46.4; n = 9) in the active arm versus -50.4 mg / dL (95% CI -106.0, +5.2; n = 3) in the placebo arm (Figure 7A, Table 3). The respective LS mean changes from baseline for glucose AUC0-4 were -590.2 hxmg / dL (95% CI -751.5, -428.9; n = 9) versus -241.1 hxmg / dL (-528.9, +46.6, n = 3) (Figure 7B, Table 3). Changes in insulin, C peptide and glucagon AUC0-4 are presented in Figures 7C, 7D and 7E respectively and Table 3). Dose-dependent bodyweight reductions were observed across all treatment groups. On day 28, in the AZD5004 50 mg cohort, the LS mean percent change from baseline in bodyweight was -5.76% (95% CI -7.43, -4.09; n = 9) in the active arm versus -3.52% (95% CI -7.01, -0.03; n = 3) in the placebo arm (Figure 7F, Table 3).

[0262] Table 3: Pharmacodynamic parameters, linear model analysis - MAD study

[0263] Percent change from

[0264] Change from baseline to

[0265] Parameters baseline to day 28, LS day 28, LS mean (95% Cl) mean (95% Cl)

[0266] Active, n = 9 -38.5 (-50.5, -26.5) -23.29 (-29.77, -16.20)

[0267] ECC5004 5 mg Placebo, n =

[0268] -24.9 (-46.1 , -3.8) -17.34 (-29.27, -3.41) 3

[0269] Active, n = 9 -49.6 (-61.6, -37.6) -28.48 (-35.12, -21.17)

[0270] Fasting 10 mg Placebo, n =

[0271] -64.8 (-85.6, -44.0) -36.75 (-46.57, -25.13) plasma 3 glucose Active, n = 9 -68.6 (-91.5, -46.1 ) -37.01 (-46.68, -25.60) (mg / dL) 30 mg Placebo, n =

[0272] -54.9 (-94.2, -15.5) -30.67 (-48.06, -7.45) 3

[0273] Active, n = 9 -76.6 (-106.8, -46.4) -40.96 (-52.06, -27.28)

[0274] 50 Placebo, n = mg -50.4 (-106.0, 5.2) -27.69 (-50.78, 6.21 ) 3

[0275] Active, n = 9 -254.2 (-362.4, -146.1 ) -26.21 (-35.94, -15.01 )

[0276] ECC5004 5 mg Placebo, n =

[0277] -207.3 (-405.6, -8.9) -22.17 (-39.91 , 0.80) 3

[0278] Active, n = 9 -286.1 (-381.6, -190.5) -28.60 (-37.26, -18.75)

[0279] 10 mg Placebo, n =

[0280] Glucose -418.5 (-584.0, -252.9) -40.13 (-52.14, -25.12) 3

[0281] AUCo^t,

[0282] Active, n = 9 -427.8 (-575.6, -280.0) -39.19 (-49.32, -27.05) hxmg / dL

[0283] 30 mg Placebo, n =

[0284] -284.3 (-540.6, -28.0) -28.84 (-48.10, -2.44) 3

[0285] Active, n = 9 -590.2 (-751.5, -428.9) -51.67 (-60.87, -40.29)

[0286] 50 Placebo, n = mg -241.1 (-528.9, 46.6) -26.12 (—49.31 , 7.68) 3

[0287] Active, n = 9 -2.99 (-3.99, -1.99) -3.28 (-4.37, -2.18)

[0288] ECC5004 5 mg Placebo, n =

[0289] -3.04 (-5.00, -1.08) -3.32 (-5.47, -1.17) 3

[0290] Active, n = 9 -3.28 (-4.58, -1.99) -3.61 (-4.96, -2.26)

[0291] 10 mg Placebo, n =

[0292] -6.51 (-8.77, -4.26) -7.02 (-9.37, -4.67)

[0293] Body weight, 3 kg Active, n = 9 -4.03 (-4.71 , -3.35) -4.90 (-5.709, -4.11 )

[0294] 30 mg Placebo, n =

[0295] -4.55 (-5.73, -3.37) -5.31 (-6.69, -3.92) 3

[0296] Active, n = 9 -4.80 (-6.22, -3.38) -5.76 (-7.43, -4.09)

[0297] 50 Placebo, n = mg -3.02 (-5.98, -0.05) -3.52 (-7.01 , -0.03) 3

[0298] Active, n = 9 -36.9 (-87.3, 13.6) -3.10 (-13.99, 9.16)

[0299] Insulin AUCo^t, ECC5004 5 mg Placebo, n =

[0300] -52.8 (-140.3, 34.7) -20.58 (-35.40, -2.37) hxmlU / L 3

[0301] 10 mg Active, n = 9 113.5 (54.4, 172.5) 40.84 (7.72, 84.13) ’ -5.7 (-109.9, 98.5) 6.92 (-33.59, 72.14)

[0302] Active, n = 9 73.1 (-10.7, 156.8) 23.58 (-11 .83, 73.21 )

[0303] 30 ma

[0304] 9Placebo n = ’ -47.0 (-192.6, 98.7) -12.96 (-51.68, 56.77)

[0305] 5()Active, n = 10 5.6 (-76.6, 87.8) 4.66 (-21 .48, 39.48)

[0306] Placebo n = mg ’ 3.3 (-143.9, 150.5) 6.94 (-35.46, 77.19)

[0307] Active, n = 9 3.47 (0.98, 5.97) 17.57 (5.13, 31.48)

[0308] ECC5004 5 mq

[0309] 9Placebo n = ’ -0.86 (-5.18, 3.46) -1.57 (-18.97, 19.56)

[0310] Active, n = 9 6.38 (2.24, 10.51 ) 36.31 (12.21 , 65.59)

[0311] 10 ma Placebo n =

[0312] C-peptide9’ 5.08 (-2.09, 12.25) 33.89 (-4.41 , 87.52) AUCo^t,

[0313] Active, n = 9 3.77 (-1.30, 8.84) 18.96 (-3.98, 47.39) hxng / mL

[0314] 30 ma

[0315] 9Placebo n = ’ -1.00 (-9.99, 7.98) -5.67 (-35.51, 37.96)

[0316] 5()Active, n = 10 2.01 (-1.80, 5.81 ) 13.09 (-4.78, 34.32)

[0317] Placebo n = mg ’ 3.34 (-3.47, 10.14) 14.50 (-15.65, 55.44)

[0318] Active, n = 9 -24.1 (-50.9, 2.8) -15.56 (-31.62, 4.27)

[0319] ECC5004 5 mq

[0320] 9Placebo n = ’ -2.6 (-50.9, 45.7) -3.07 (-33.96, 42.28)

[0321] Active, n = 9 -98.8 (-143.1 , -54.5) -36.92 (-50.34, -19.88)

[0322] 10 ma Placebo n =

[0323] Glucagon9’ -230.3 (-313.4, -147.2) -69.83 (-80.56, -53.17)

[0324] AUCo-t,

[0325] Active, n = 9 -107.4 (-143.4, -71.4) -48.12 (-58.55, -35.07) hxpg / mL

[0326] 30 ma

[0327] 9Placebo n = ’ -65.5 (-129.8, -1.2) -24.96 (-49.86, 12.29)

[0328] 5()Active, n = 10 -75.6 (-101.1 , -50.1) -40.76 (-53.40, -24.70)

[0329] Placebo n = mg ’ -69.5 (-113.8, -25.1 ) -35.11 (-57.31 , -1 .38)

[0330] AUC0-4: area under the plasma-concentration curve from time 0 to 4 hours post-dose; CI, confidence interval; LS, least square.

[0331] Pharmacodynamic analyses The parameters used to assess the pharmacodynamics of AZD5004 include: area under the plasma concentration-time curve from time 0 to 2- and 4-hours post-dose (AUCO-2 or AUCO-4) for glucose, insulin, glucagon and C-peptide, change from baseline in FPG, mean daily glucose levels (MDG), fasting plasma insulin (FPI) levels, bodyweight and waist circumference. Data were analysed for each participant using Mixed-Meal Tolerance Test (MMTT), Oral Glucose Tolerance Test (OGTT), Homestoatic Model Assessment for Insulin Resistance (HOMO-IR) as appropriate. Plasma glucose levels were assessed at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 and 24 hours post mixed-meal on Days -1, 14 and 28; plasma insulin, C-peptide and glucagon levels were assessed at pre-dose and 0.25, 0.5, 1, 1,5, 2, 3, 4, hours post mixed-meal on Days -1, 14 and 28. All participants took a standard MMTT on Days -1, 14 and 28.

[0332] Example 4: Food Effect Study

[0333] An open-label, randomized, single-dose study was performed in 14 healthy participants under fasted (> 10 hours) conditions, or following a standardized high-fat breakfast (800-1000 calories with at least 50% of the caloric content derived from fat) consumed within 30 minutes with 7 days washout in between treatment periods (Figure 8A).

[0334] ECC5004 was administered within 30 minutes of the start of the meal in the fed condition. Serial plasma concentrations of ECC5004 were measured for 120 hours following a single dose of ECC5004 50 mg and PK parameters were derived and compared for each condition.

[0335] Disposition and baseline characteristics

[0336] Of the 23 participants screened, 14 were randomized, one participant was discontinued due and 13 (92.9%) completed the study. All participants were healthy volunteers and were predominantly male (71.4%) and White (85.7%). Participants had a mean age of 46.7 years (SD 12.5) and a mean body mass index of 27.1 kg / m2 (SD 3.2).

[0337] Pharmacokinetics

[0338] The PK characteristics support once-daily dosing (Figure 8B and Table 4). There were no statistically significant differences under fed or fasted conditions for AUCiast (geometric mean ratio [RoGM] 1.05; 90% confidence interval [CI]: [0.9, 1.23], with fasted state as reference), elimination half-life (tl / 2) (0.97; [0.94, 1.04]), time to maximum concentration (tmax) (1.21; [0.88, 1.67]) and maximum concentration (Cmax) (0.87; [0.69, 1.11]) (Figure 8C).

[0339] Table 4: Fed / Fasted Phamacokinetic Parameters

[0340] AUCiast, Cmax, ng / mL tinax hr GM ti / i, hr GM

[0341] Arms ng hr / mL GM (CV%) (CV%) (CV%) GM (CV%)

[0342] 50 mg fasted 11443.21 374.5 8.8 21.2 (n = 14) (56.22) (53.6) (42.2) (19.1)

[0343] 50 mg fed 12054.39 326.9 10.7 20.7 (n = 14) (65.48) (51.1) (54.3) (14.7)

[0344] CV, coefficient of variation; Cmax, maximum concentration; GM, geometric mean; ti / 2, elimination half-life time; tmax, time to maximum concentration.

[0345] Safety and tolerability

[0346] There were no serious adverse events, deaths, or discontinuations due to treatment emergent AEs. The overall frequency of adverse events (AEs) was 64.3% in the fed state and 50% in the fasted state. The most common AEs were nausea, dyspepsia, abdominal discomfort, and vomiting. There were no clinically relevant treatment-emergent abnormalities on laboratory assessments or ECGs.

[0347] Example 5: Phase lib Clinical Trial for AZD5004 in adults with T2DM

[0348] A Phase lib, global, randomized, parallel-group, double-blind, placebo-controlled study with an open-label active comparator (oral semaglutide) arm has been designed to evaluate the efficacy, safety, and tolerability of 5, 15, 25, 50, and 100 mg of AZD5004, in adults with T2DM and an HbAlc of > 7.0% and < 10.5%. The primary endpoint will be evaluated after all participants have completed 26 weeks of treatment.

[0349] Participants will be > 18 years of age with HbAlc > 7.0% and < 10.5%. Following a 7 day placebo lead-in, participants who are eligible according to the inclusion / exclusion criteria will be randomized in a 3:5:3:5:3:3:6:4 ratio to receive AZD5004, matched placebo, or semaglutide (Rybelsus®). AZD5004 will be administered at doses of 5, 15, and 25 mg as flat doses and 50 mg (every 2 weeks (Q2W) titration), 100 mg [Q2W titration], and 100 mg (every 4 weeks [Q4W] titration). The number of participants being randomized to each treatment arm is presented in Error! Reference source not found.. Semaglutide (Rybelsus®) 14 mg will be given once daily (qd) as open-label active treatment reference arm (titration as per prescription. Each AZD5004 treatment group will be placebo-matched with respect to titration schedule and dose levels.

[0350] Participation in the study will last for approximately 30 weeks in total, with participants receiving treatment for 26 weeks during that time. The study will include a screening period and placebo lead-in period each of approximately 7 days (14 days in total), followed by a doubleblind treatment period of 26 weeks. A follow-up visit will be conducted approximately 14 days post the last dose. Following a 7 day placebo lead-in, participants will be randomized to receive 5, 15, 25, 50, or 100 mg of AZD5004, placebo matched to the AZD5004 arms, or semaglutide (Rybelsus® 14 mg qd (titrated as per label) as an open-label active comparator reference arm). The AZD5004 5, 15, and 25 mg arms will not require titration, whereas the 50 and 100 mg treatment arms will be titrated according to a Q2W or Q4W schedule (Error! Reference source not found.). The titration regimens are detailed in Table . Participants will be given the opportunity to temporarily down-titrate during the study upon experiencing any potential tolerability issues.

[0351] Table 5 Titration Regimen lOOmg A, every 2 weeks titration; lOOmg B, every 4 weeks titration; Wk, week.

[0352] The objectives and endpoints are presented in Table 6.

[0353] Table 6: Objectives and Endpoints

[0354] AE, adverse event; AESI, adverse eventof special interest; CSR, clinical study report; DAE, AE leading to discontinuation of IMP; DTSQs, diabetes treatment satisfaction questionnaire - status version; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; HbAlc, hemoglobin Ale; HDL- C, high-density lipoprotein-cholesterol; hsCRP, high sensitivity C-reactive protein; IMP, investigational product; LDL-C (Calc), low-density lipoprotein-cholesterol (calculated); MACE, major adverse cardiovascular event; NEFA, non-esterified fatty acid; PD, pharmacodynamic; PK, pharmacokinetic; SAE(s), serious adverse event(s); uACR, urine albumin-creatinine ratio; VLDL-C (Calc), very low-density lipoprotein-cholesterol (calculated).

[0355] The current study will enrol participants with T2DM who have inadequate glycemic control based on HbAlc values ranging from 7.0% to 10.5%, inclusive, with lifestyle alone or metformin or an SGLT2 inhibitor. Participants who are treatment naive or on a stable dose of metformin or SGLT2 inhibitor therapy can be enrolled if they satisfy all inclusion and exclusion criteria. The study population is expected to represent participants in the likely clinical use setting. To minimize the potential confounding effect of changes in concomitant medications, participants will be permitted to use concomitant medications that do not interfere with the assessment of efficacy or safety characteristics of the study treatments.

[0356] Inclusion Criteria:

[0357] • Adults > 18 years of age.

[0358] • Diagnosed with T2DM for at least 6 months.

[0359] • HbAlc > 7.0% and < 10.5% managed with diet and exercise alone or with a stable dose of metformin or an SGLT2 inhibitor for at least one month prior to screening.

[0360] • Body mass index of > 23 kg / m2.

[0361] • Stable self-reported body weight for 3 months prior to randomization (+ / - 5% body weight change).

[0362] Exclusion Criteria:

[0363] • Type 1 diabetes mellitus, secondary forms of diabetes or history of ketoacidosis or hyperosmolar coma.

[0364] • History of proliferative diabetic retinopathy, diabetic maculopathy, or severe nonproliferative diabetic retinopathy that required immediate treatment.

[0365] • Have had more than one episode of severe hypoglycemia within 6 months prior to screening, or has a history of hypoglycemia unawareness or poor recognition of hypoglycemic symptoms.

[0366] • Received medication for weight loss within the last 3 months prior to screening.

[0367] • Clinically significant inflammatory bowel disease, gastroparesis, severe disease or surgery affecting the upper GI tract.

[0368] • Previous or planned (within study period) bariatric surgery or fitting of a weight loss device (eg, gastric balloon or duodenal barrier).

[0369] • History of acute or chronic pancreatitis.

[0370] All participants will be centrally assigned to randomized study intervention. Participants will be stratified at randomization according to the following 3 strata:

[0371] Participants on SGLT2 inhibitor therapy • Participants not on SGLT2 inhibitor therapy with HbAlc < 8%

[0372] • Participants not on SGLT2 inhibitor therapy with HbAlc > 8%

[0373] Use of SGLT2 inhibitor therapy is assessed at the time of randomization. HbAlc stratum is determined using the most recent HbAlc (%) measurement available at the time of randomization.

[0374] Participants who were on baseline metformin or SGLT2 inhibitor therapy at randomization should continue on their dose as prescribed. Other medications prescribed for treatment of comorbidites associated with T2DM should also continue as prescribed. Participants should receive full supportive care during the study in accordance with their institutional guidelines. If nausea or vomiting occurs, participants should be encouraged to reduce oral intake of food until symptoms resolve. In the event that symptoms do not improve, participants should be offered anti-emetic therapy or laxative or antidiarrheal medication in accordance with institutional and local practice guideline; however, prokinetic agents such as domperidone or metoclopramide should be avoided unless a centrally acting antiemetic has been deemed ineffective or not tolerated by the participant.

[0375] Use of the following medications will be restricted as described in Table 7.

[0376] Table 7: Restricted Concomitant Medications

[0377] The following medications will be prohibited from the start of screening until the end of the study:

[0378] • GLP-lRAs and GLP-1RA containing therapies (as well as within the 3 months prior to screening,

[0379] • Drugs approved for weight loss (eg, orlistat, bupropion / naltr exone, phenterminetopiramate, phentermine, semaglutide, tirzepatide) as well as those drugs used off-label (as well as within the 3 months prior to screening,

[0380] • Strong CYP3A4 inhibitors (e.g., ceritinib, clarithromycin, cobicistat,elvitegravir, ritonavir, idelalisib, indinavir and ritonavir, Itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir, ombitasvir and / or dasabuvir, posaconazole, ritonavir, saquinavir and ritonavir, telithromycin, tipranavir and ritonavir, voriconazole, boceprevir, danoprevir and ritonavir, elvitegravir and ritonavir, ensitrelvir, indinavir, josamycin, lonafarnib, mibefradil, mifepristone, nirmatrelvir and ritonavir, ombitasvir and paritaprevir and ritonavir, ombitasvir and paritaprevir and ritonavir and dasabuvir, relacorilant, saquinavir, saquinavir and ritonavir, telaprevir, troleadomycin)

[0381] • Moderate CYP3A4 inhibitors (e.g., aprepitant, ciprofloxacin, conivaptan, crizotinib, diltiazem, dronedarone, erythromycin, fluconazole, grapefruit juice, imatinib, isavuconazole, verapamil, amprenavir, atazanavir, atazanavir and ritonavir, berotralstat, carotegrast methyl, casopitant, clofazimine, darunavir, darunavir and ritonavir, faldaprevir, fosravuconazole, Lefamulin, lenacapavir, letermovir, netupitant, nivasorexant, ravuconazole, ritlecitinib, tofisopam, voxelotor, ziritaxestat)

[0382] • Strong CYPA4 inducers (e.g.,apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor and ivacaftor, mitotane, phenytoin, rifampin, St. John’s wort, Avasimibe, lumacaftor, rifapentine)

[0383] • Moderate CYPA4 inducers (e.g.,bosentan, cenobamate, dabrafenib, efavirenz, etravirine, lorlatinib, pexidartinib, phenobarbital, primidone, sotorasib,

[0384] • asunaprevir and beclabuvir and daclatasvir, bersacapavir, elagolix, lersivirine, lesinurad, lopinavir, metamizole (dipyrone), mitapivat, modafinil, nafcillin, rifabutin, semagacestat, talviraline, telotristat ethyl, thioridazine, tipranavir and ritonavir) • Central Nervous System Stimulants (e.g., methylphenidate).

[0385] • Sensitive or moderately sensitive CYP2C8 substrates (e.g., repaglinide, montelukast, pioglitazone, rosiglitazone, daprodustat, dasabuvir, selexipag, desloratadine (descarboethoxyloratadine), enzalutamide, loperamide, paclitaxel, pemafibrate, resmetirom, tucatinib)

[0386] • Sensitive or moderately sensitive CYP2B6 substrates (e.g, bupropion, cyclophosphamide, efavirenz, nevirapine, sibutramine, (S)-methadone, (S)-sibutramine, esketamine, ketamine)

[0387] • Other breast cancer resistant protein (BCRP) substrates (e.g., coumestrol, daidzein, genistein, prazosin, sulphasalazine, ozanimod, teriflunomide, sofosbuvir, sunitinib, teriflunomide)

[0388] • Narrow Therapeutic Index drugs that are P-gp substrates (digoxin), other P-gp substrates will be allowed

[0389] • Narrow therapeutic index drugs that are CYP3 A4 substrates (e.g., alfentanil, astemizole, carbamazepine, cisapride, colchicine, cyclosporin, dihidroergotamine, ergotamine, docetaxel, ethenylestradiol, everolimus, fentanyl, pimozide, quinidine, quinine, sirolimus, tacrolimus, terfenadine)

[0390] • Estrogen-containing products

[0391] • Pitavastatin

[0392] • Sensitive CYP3A4 substrates (e.g., alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, dronedarone, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, isavuconazole, ivabradine, lemborexant, lomitapide, lurasidone, maraviroc, midazolam, mobocertinib, naloxegol, nisoldipine, quetiapine, saquinavir, sildenafil, ticagrelor, tipranavir, tolvaptan, triazolam, vardenafil, venetoclax)

[0393] Samples for assessment of HbAlc will be collected at certain times throughout the study.

[0394] Samples for assessment of fasting glucose, insulin, and c-peptide will be collected certain times throughout the study.

[0395] Body weight should be measured in a consistent manner, at approximately the same time throughout the study whenever possible, after emptying the bladder. The participant’s weight should be measured without shoes and only wearing light clothing (no heavy jumpers / sweaters / outer garments). Body weight should be measured in kilograms (kg) and recorded to one decimal place. The same scale should be used for all assessments for a given participant and calibrated on a regular basis as recommended by the manufacturer. BMI will be calculated as the weight in kilograms (kg) divided by the square of height in meters (kg / m2). The height measurement recorded at Screening and the current body weight measurement recorded for the specified visit will be used for that visit’s BMI calculation.

[0396] All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety for all purposes.

Claims

CLAIMS1. A method of treating type 2 diabetes mellitus (T2DM) in a subject in need thereof, comprising administering to the subject a once daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the once daily dose is from 5 mg to 75 mg.

2. The method of claim 1, wherein the once daily dose of AZD5004, or pharmaceutically acceptable salt thereof, is selected from 5mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 55 mg, 65 mg, and 75 mg.

3. A method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising six consecutive escalating dosing periods followed by a target dosing regimen, wherein the method comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 2.5 mg to 5 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 5 mg to 10 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 10 mg to 15 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 15 mg to 25 mg,e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 25 mg to 35 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 2 weeks, wherein the sixth once-daily dose is 35 mg to 45 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 45 mg to 100 mg.

4. The method of claim 3, wherein: a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 2.5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 15 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 25 mg; f) the sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 35 mg; and g) the target once-daily dose is 50 mg.

5. The method of claim 3, wherein:a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 30 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 40 mg; f) the sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 50 mg; and g) the target once-daily dose is 65 mg.

6. A method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising six consecutive escalating dosing periods followed by a target dosing regimen, wherein the method comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg to 15 mg,c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 20 mg to 35 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 35 mg to 50 mg, f) after the fifth dosing period, administering a sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a sixth dosing period of 4 weeks, wherein the sixth once-daily dose is 45 mg to 60 mg, and g) after the sixth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 60 mg to 80 mg.

7. The method of claim 6, wherein: a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 30 mg;e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 40 mg; f) the sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 55 mg; and g) the target once-daily dose is 75 mg.

8. The method of claim 6, wherein: a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 30 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 40 mg; f) the sixth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 50 mg; and g) the target once-daily dose is 65 mg.

9. A method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising five consecutive escalating dosing periods followed by a target dosing regimen, wherein the method comprises:a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 2 weeks, wherein the first once-daily dose is 5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 2 weeks, wherein the second once-daily dose is 10 mg to 15 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 2 weeks, wherein the third once-daily dose is 15 mg to 25 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 2 weeks, wherein the fourth once-daily dose is 25 mg to 50 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 2 weeks, wherein the fifth once-daily dose is 50 mg to 80 mg, f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 75 mg to 100 mg.

10. The method of claim 9, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg;d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 40 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 75 mg; and f) the target once-daily dose is 100 mg.

11. A method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising five consecutive escalating dosing periods followed by a target dosing regimen, wherein the method comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 15 mg to 30 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 20 mg to 40 mg, e) after the fourth dosing period, administering a fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fifth dosing period of 4 weeks, wherein the fifth once-daily dose is 35 mg to 55 mg,f) after the fifth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 45 mg to 75 mg.

12. The method of claim 11, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 15 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 25 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 40 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 55 mg; and f) the target once-daily dose is 75 mg.

13. The method of claim 11, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg;d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 35 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is45 mg; and f) the target once-daily dose is 65 mg.

14. The method of claim 11, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 30 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is45 mg; and f) the target once-daily dose is 65 mg.

15. The method of claim 11, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg;c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 15 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 25 mg; e) the fifth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 35 mg; and f) the target once-daily dose is 50 mg.

16. A method of treating T2DM in a subject in need thereof, comprising orally administering to the subject a once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, comprising four consecutive escalating dosing periods followed by a target dosing regimen, wherein the method comprises: a) administering a first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a first dosing period of 4 weeks, wherein the first once-daily dose is 5 mg to 10 mg, b) after the first dosing period, administering a second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a second dosing period of 4 weeks, wherein the second once-daily dose is 10 mg to 20 mg, c) after the second dosing period, administering a third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a third dosing period of 4 weeks, wherein the third once-daily dose is 20 mg to 35 mg, d) after the third dosing period, administering a fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, for a fourth dosing period of 4 weeks, wherein the fourth once-daily dose is 30 mg to 50 mg,e) after the fourth dosing period, administering a target once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof, wherein the target once-daily dose is 40 mg to 75 mg.

17. The method of claim 16, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 15 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 30 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 45 mg; and e) the target once-daily dose is 65 mg.

18. The method of claim 16, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 35 mg; and e) the target once-daily dose is 50 mg.

19. The method of claim 16, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 35 mg; and e) the target once-daily dose is 45 mg.

20. The method of claim 16, wherein a) the first once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 5 mg; b) the second once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 10 mg; c) the third once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 20 mg; d) the fourth once-daily dose of AZD5004, or a pharmaceutically acceptable salt thereof is 30 mg; and e) the target once-daily dose is 45 mg.

21. The method of any one of claims 1-20, wherein the subject is human.

22. The method of any one of claims 1-21, wherein the subject has chronic kidney disease.

23. The method of any one of claims 1-22, wherein the subject has an initial HbAlc equal to or greater than 6.5%.

24. The method of claim 23, wherein the subject as an initial HbAlc equal to or greater than 7.0%.

25. The method of claim 23, wherein the subject as an initial HbAlc equal to or greater than 7.5%.

26. The method of claim 23, wherein the subject as an initial HbAlc equal to or greater than 8.0 %.

27. The method of any of claims 1-26 wherein the subject’s initial HbAlc is lowered by at least 1.0%, 1.5%, or 2.0%.

28. The method of any of claims 1-27, where in the subject has an initial BMI greater than 25 kg / m2, 26 kg / m2, 27 kg / m2, 28 kg / m2, 29 kg / m2, or 30 kg / m2.

29. The method of any of claims 1-28 wherein the subject’s initial BMI is lowered by at least 0.5 kg / m2, 1 kg / m2, 1.5 kg / m2, 2 kg / m2, 2.5 kg / m2, 3 kg / m2, 3.5 kg / m2, 4 kg / m2, 4.5 kg / m2, 5 kg / m2, 5.5 kg / m2, 6 kg / m2, 7.5 kg / m2, 8 kg / m2, 9 kg / m2, 10 kg / m2, 12 kg / m2, or 15 kg / m2.

30. The method of any of claims 1-29, wherein the subject is administered AZD5004.

31. The method of any of claims 1-29, wherein the subject is administered a pharmaceutically acceptable salt of AZD5004.

32. The method of any of claims 1-31, comprising further administering to the subject a statin, wherein the statin is administered at the lowest recommended dose.

33. The method of claim 32, wherein the statin is rosuvastatin and is administered at 10 mg a day or less.

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