Methods of treating metabolic diseases with glp-1 analogs and medical uses

Abstract

Methods of treating metabolic diseases with GLP-1 analogs and medical uses. In particular, methods of preventing or treating metabolic diseases comprising once-weekly administration of a GLP-1 analog or a pharmaceutically acceptable salt thereof.

Description

Methods and medical uses of GLP-1 analogs for treating metabolic diseases

[0001] This disclosure claims priority from the following Chinese patent applications:

[0002] CN202311696184.5 and CN202311696354.X, filed on December 12, 2023;

[0003] CN202410264918.0 and CN202410265036.6, filed on March 8, 2024;

[0004] CN202410900383.1, CN202410900557.4, CN202410899570.2, and CN202410899701.7, filed on July 5, 2024;

[0005] CN202411248832.5 and CN202411249019.X filed on September 6, 2024; and

[0006] CN202411450978.8 and CN202411451040.8 filed on October 17, 2024. Technical Field

[0007] The present disclosure belongs to the field of medicine and relates to methods and medical uses of GLP-1 analogs for treating metabolic diseases. Background Art

[0008] GLP-1 and GIP are polypeptide hormones synthesized and secreted by the intestine after a meal. Both are incretins. Their primary physiological effect is to stimulate insulin release in a glucose-dependent manner by activating corresponding receptors on pancreatic beta cells. Both the GLP-1 and GIP receptors are members of the G protein-coupled receptor class B family and share similar structures.

[0009] GLP-1 is primarily secreted by L cells in the ileum and colon. Its active forms are primarily GLP-1(7-36) and GLP-1(7-37), derived from preproglucagon through translational cleavage and sharing 50% homology with glucagon. GLP-1 receptors are widely distributed in the pancreatic islets, intestines, and central nervous system, and are also expressed in the lungs, heart, kidneys, and immune cells. In the pancreatic islets, GLP-1 stimulates insulin release from β cells and inhibits glucagon secretion from α cells in a glucose-dependent manner, thereby lowering blood sugar. Expression in other areas of the pancreas has benefits such as appetite suppression, delayed gastric emptying, improved memory, and cardiovascular protection.

[0010] GIP is primarily secreted by K cells in the duodenum and proximal small intestine, with receptors primarily located in pancreatic islets, white fat, bones, and the central nervous system. In addition to its glucose-dependent insulin-secreting effect, GIP can promote glucagon secretion in hypoglycemia and inhibit glucagon secretion in hyperglycemia. It also improves lipid metabolism, insulin resistance, and appetite.

[0011] The mechanisms of action of GLP-1 and GIP are both overlapping and complementary. Simultaneous stimulation of GLP-1 and GIP receptors may further promote insulin secretion, suppress appetite, and improve insulin resistance. In recent years, several single-molecule GLP-1 / GIP dual receptor agonists have entered clinical development. Among them, the fastest-progressing is Eli Lilly's Tirzepatide, which was approved by the FDA for the treatment of type 2 diabetes in May 2022 and approved for weight loss indications in November 2023. The results of clinical trials of Tirzepatide showed that Tirzepatide has better potential for lowering blood sugar and reducing weight than GLP-RAs such as dulaglutide and semaglutide, with good safety, and the main adverse reactions are gastrointestinal events (nausea, diarrhea, loss of appetite, vomiting, etc.). However, the instructions for Tirzepatide recommend maintenance doses of 5mg, 10mg, and 15mg, with a dosing frequency of once a week.

[0012] Therefore, developing new treatment options with reduced dosing frequency, safety, and effectiveness for dual-target agonists of GLP-1 and GIP is an important issue that needs to be addressed urgently. Summary of the Invention

[0013] The present disclosure provides methods and medical uses of GLP-1 analogs for treating metabolic diseases.

[0014] In a first aspect, the present disclosure provides a novel dosing regimen for a GLP-1 analogue or a pharmaceutically acceptable salt thereof.

[0015] In a second aspect, the present disclosure provides a method for preventing or treating metabolic diseases, comprising administering a target drug selected from a GLP-1 analogue or a pharmaceutically acceptable salt thereof to a subject in need thereof according to the following dosing regimen.

[0016] In a third aspect, the present disclosure provides a method for improving weight control in a subject in need thereof, comprising administering a target drug selected from a GLP-1 analogue or a pharmaceutically acceptable salt thereof to the subject in need thereof according to the following dosing regimen.

[0017] In a fourth aspect, the present disclosure provides a method for improving glycemic control in a subject in need thereof, comprising administering a target drug selected from a GLP-1 analogue or a pharmaceutically acceptable salt thereof to the subject in need thereof according to the following dosing regimen.

[0018] Fifth aspect, the present disclosure provides a method for improving blood lipid control in a subject in need, comprising administering a target drug to the subject in need according to the following dosing regimen, wherein the target drug is selected from GLP-1 analogs or pharmaceutically acceptable salts thereof.

[0019] Sixth aspect, the present disclosure provides a target drug, which is administered to a subject in need according to the following dosing regimen, and the target drug is used for:

[0020] 1) Preventing or treating metabolic diseases; 2) improving weight control in a subject in need; 3) improving blood glucose control in a subject in need; 4) improving blood lipid control in a subject in need. In some embodiments, the subject in need has a metabolic disease.

[0021] In some embodiments, the metabolic disease is selected from obesity or overweight. In some embodiments, the subject has a BMI ≥ 28.0 kg / m 2 and / or a BMI ≤ 40.0 kg / m 2 .

[0022] In some embodiments, the subject is obese or overweight and has at least one weight-related comorbidity. In some embodiments, the comorbidity includes one or more of prediabetes, hypertension, and dyslipidemia. In some embodiments, the subject has a BMI ≥ 24.0 kg / m 2 and / or a BMI < 28.0 kg / m 2 , and has at least one weight-related comorbidity, for example, the comorbidity includes one or more of prediabetes, hypertension, and dyslipidemia.

[0023] In some embodiments, the prediabetic subjects include impaired fasting glucose, impaired glucose tolerance, and a mixed state of both.

[0024] In some embodiments, the prediabetic subjects are subjects with a fasting blood glucose of 6.1 mmol / L < fasting blood glucose < 7.0 mmol / L, or subjects with an HbAlc of 5.7% < HbAlc < 6.5%.

[0025] In some embodiments, the metabolic disease is diabetes.

[0026] In some embodiments, the metabolic disease is type 2 diabetes.

[0027] In some embodiments, the HbA1c of the type 2 diabetic subjects is ≥ 7.5% and / or HbA1c ≤ 11%.

[0028] In some embodiments, the type 2 diabetes subject is one for whom lifestyle intervention alone (e.g., diet and / or exercise control) remains ineffective, for example, poor glycemic control remains despite lifestyle intervention alone, or for example, one for whom the target HbA1c cannot be achieved after lifestyle intervention alone. In some embodiments, the type 2 diabetes subject is one for whom HbA1c remains greater than 7% after lifestyle intervention alone, for example, HbA1c ≥ 7.5%.

[0029] In some embodiments, the subject with type 2 diabetes is one who is still experiencing poor results with metformin treatment, e.g., one who is still experiencing poor glycemic control with metformin treatment, e.g., one who is unable to achieve target HbA1c with metformin treatment. In some embodiments, the subject has an HbA1c > 7% after metformin treatment, e.g., an HbA1c ≥ 7.5%.

[0030] In some embodiments, the subject with type 2 diabetes is one who has not responded well to metformin combined with an SGLT2 inhibitor, for example, one who has not achieved adequate glycemic control despite treatment with metformin combined with an SGLT2 inhibitor, or one who has not been able to achieve target HbA1c despite treatment with metformin combined with an SGLT2 inhibitor. In some embodiments, the subject has an HbA1c > 7% after treatment with metformin combined with an SGLT2 inhibitor, for example, an HbA1c ≥ 7.5%.

[0031] In some embodiments, the subject with type 2 diabetes who is receiving the target medication is also administered metformin.

[0032] In some embodiments, the subject with type 2 diabetes who is receiving the target medication is also administered metformin, which is the original stable treatment.

[0033] In some embodiments, the subject with type 2 diabetes who is receiving the target medication is also administered metformin and an SGLT2 inhibitor.

[0034] In some embodiments, the subject with type 2 diabetes who is receiving the target medication is also receiving stable treatment with metformin and an SGLT2 inhibitor.

[0035] In some embodiments, stable treatment is defined as receiving the target drug before treatment (metformin and SGLT2 inhibitor) and the total daily dose has not changed, for example, the metformin dose is ≥1500 mg / day or the maximum tolerated dose (≥1000 mg / day); the SGLT2 inhibitor dose is the daily dose recommended in the instructions.

[0036] In some embodiments, the subject with type 2 diabetes has a BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[0037] In some embodiments, the type 2 diabetes subject is obese.

[0038] In some embodiments, the type 2 diabetic subject is non-obese.

[0039] In some embodiments, the subject with type 2 diabetes is at least one of the following:

[0040] 1) Patients whose disease is poorly controlled by lifestyle intervention alone (such as diet and / or exercise control) or metformin;

[0041] 2) HbA1c ≥ 7.5% and / or HbA1c ≤ 10.5%;

[0042] 3) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[0043] In some embodiments, the subject with type 2 diabetes is at least one of the following:

[0044] 1) Patients whose blood sugar is still poorly controlled despite treatment with metformin or metformin combined with SGLT2 inhibitors;

[0045] 2) HbA1c ≥ 7.5% and / or HbA1c ≤ 11%;

[0046] 3) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[0047] In some embodiments, the diabetic subject is at least one of the following:

[0048] 1) Currently taking metformin or metformin combined with SGLT2 inhibitors;

[0049] 2) HbA1c ≥ 7.5% and / or HbA1c ≤ 11%;

[0050] 3) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[0051] <Dosage regimen>

[0052] In some embodiments, the dosing regimen I comprises administering the drug of interest about once a week.

[0053] In some embodiments, the dosing regimen II comprises:

[0054] During the first treatment period, the drug of interest is administered approximately once per week; and

[0055] During the second treatment period, the drug of interest is administered approximately once every two weeks or once per week.

[0056] First treatment period of regimen I or regimen II

[0057] In some embodiments, the first treatment period comprises:

[0058] administering an initial dose of the drug of interest once a week for at least about 1 week, and subsequently,

[0059] administering increasing doses of the drug of interest once weekly for at least about 1 week, followed by

[0060] A maintenance dose of the drug of interest is administered once per week for at least about 2 weeks.

[0061] or,

[0062] administering an initial dose of the drug of interest once a week for at least about 1 week, and subsequently,

[0063] A maintenance dose of the drug of interest is administered once per week for at least about 2 weeks.

[0064] In some embodiments, the initial dose is selected from about 0.1 mg to about 2.5 mg, or about 0.5 mg to about 1.5 mg; or any range between these points. In some embodiments, the initial dose is selected from about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg; or any range between any of the above points. In some embodiments, the initial dose is selected from about 0.5 mg, about 1.0 mg, or about 1.5 mg.

[0065] In some embodiments, the ascending dose is selected from about 0.5 mg to about 10.0 mg, about 1.0 mg to about 10.0 mg, about 1.0 mg to about 6.0 mg, about 1.0 mg to about 5.0 mg, about 2.0 mg to about 5.0 mg, about 2.0 mg to about 4.0 mg, about 2.0 mg to about 3.0 mg, about 2.0 mg to about 2.5 mg, about 1.0 mg to about 7.5 mg, about 1.0 mg to about 4.5 mg, about 1.5 mg to about 4.5 mg, about 2.0 mg to about 4.5 mg, about 3.0 mg to about 5.0 mg, about 3.0 mg to about 4.5 mg, about 4.0 mg to about 6.0; or any range between these points.

[0066] In some embodiments, the increasing dose is selected from about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5. 5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, about 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, about 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg, about 7.8mg, about 7 .9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10.0 mg; or any range between these point values. In some embodiments, the increasing dose is selected from about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg or about 6.0 mg.

[0067] In some embodiments, the ascending doses include a second dose, or a second dose and a third dose, or a second dose, a third dose, and a fourth dose, or a second dose, a third dose, a fourth dose, and a fifth dose, or a second dose, a third dose, a fourth dose, a fifth dose, and a sixth dose.

[0068] In some embodiments, the second dose is selected from about 1.0 mg to about 5.0 mg, about 1.0 mg to about 3.0 mg, or about 2.0 mg to about 3.0 mg. In some embodiments, the second dose is selected from about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3. In some embodiments, the second dose is selected from about 2.0 mg or about 3.0 mg.

[0069] In some embodiments, the third dose is selected from about 1.0 mg to about 7.5 mg, about 1.0 mg to about 4.5 mg, about 2.0 mg to about 4.5 mg, or about 3.0 mg to about 4.5 mg. In some embodiments, the third dose is selected from about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg , about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, or any range therebetween. In some embodiments, the third dose is selected from about 3.0 mg, about 4.0 mg, or about 4.5 mg.

[0070] In some embodiments, the fourth dose is selected from about 1.0 mg to about 9.0 mg, about 1.0 mg to about 4.0 mg, or about 2.0 mg to about 4.0 mg, or about 4.0 mg to about 5.0 mg. In some embodiments, the fourth dose is selected from about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg. , about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, or any range therebetween. In some embodiments, the fourth dose is selected from about 4.0 mg or about 5.0 mg.

[0071] In some embodiments, the fifth dose or the sixth dose is selected from about 1.0 mg to about 11.0 mg, about 1.0 mg to about 4.0 mg, or about 2.0 mg to about 4.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0 mg. In some embodiments, the fifth dose or the sixth dose is selected from about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg , about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4.0mg, about 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5.0mg, about 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg g, about 5.9 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 In some embodiments, the fifth dose is about 5.0 mg or about 6.0 mg. In some embodiments, the sixth dose is about 6.0 mg.

[0072] In some embodiments, the maintenance dose is selected from about 0.5 mg to about 10.0 mg, about 3.0 mg to about 10.0 mg, about 1.0 mg to about 10.0 mg, about 1.0 mg to about 8.0 mg, about 1.0 mg to about 6.0 mg, about 1.0 mg to about 5.0 mg, about 2.0 mg to about 6.0 mg, about 3.0 mg to about 6.0 mg, about 4.0 mg to about 6.0 mg or about 4.5 mg to about 6.0 mg. In some embodiments, the maintenance dose is selected from about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg. , about 2.8mg, about 2.9mg, about 3.0mg, about 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4.0mg, about 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5.0mg, about 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, about 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, about 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg, about In some embodiments, the maintenance dose is selected from about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg, or 8.0 mg.

[0073] In some embodiments, the initial dose of the target drug is administered once per week for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, etc. For example, the initial dose is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, etc. In some embodiments, the initial dose of the target drug is administered for about 4 weeks.

[0074] In some embodiments, the increasing dose of the drug of interest is administered once per week for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 8 weeks, etc. For example, the increasing doses are administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, etc. In some embodiments, the increasing doses of the drug of interest are administered for about 4 weeks, about 8 weeks, or about 16 weeks. In some embodiments, each increasing dose of the drug of interest is administered for at least about 4 weeks.

[0075] In some embodiments, a maintenance dose of the drug of interest is administered once per week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, etc. For example, a maintenance dose is administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, etc. In some embodiments, during the first treatment period, a maintenance dose of the drug of interest is administered once per week for about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, or about 28 weeks, about 32 weeks, about 36 weeks, about 38 weeks, or about 48 weeks.

[0076] In some embodiments, the duration of the first treatment period is at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, at least 26 weeks, at least 28 weeks, at least 30 weeks, at least 34 weeks, at least 36 weeks, at least 38 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 50 weeks, etc.

[0077] In some embodiments, the duration of the first treatment period of Dosing Regimen I or Dosing Regimen II is about 24 weeks or about 36 weeks.

[0078] In some embodiments, the dosing regimen I or first treatment period I-1 comprises:

[0079] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0080] d) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0081] or,

[0082] a) administering an initial dose of the target drug once weekly for at least about 1 week, followed by

[0083] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0084] d) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0085] or,

[0086] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0087] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0088] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0089] d) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0090] or,

[0091] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0092] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0093] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0094] Administer a fourth dose of the target drug weekly for at least about 2 weeks, followed by

[0095] Administer the fifth dose of the target drug weekly for at least about 2 weeks, followed by

[0096] d) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0097] or,

[0098] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0099] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0100] c) administering a third dose of the drug of interest once weekly for at least about 1 week, followed by

[0101] Administer a fourth dose of the target drug weekly for at least about 1 week, followed by

[0102] Administer the fifth dose of the target drug weekly for at least about 1 week, followed by

[0103] Administer the sixth dose of the target drug weekly for at least about 1 week, followed by

[0104] d) administering a maintenance dose of the target drug once weekly for at least about 2 weeks.

[0105] In some embodiments, the dosing regimen 1 or first treatment period 1-2 comprises:

[0106] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0107] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0108] or,

[0109] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0110] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0111] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0112] or,

[0113] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0114] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0115] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0116] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0117] or,

[0118] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0119] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0120] c) administering a third dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0121] Administer a fourth dose of the target drug weekly for at least about 4 weeks, followed by

[0122] Administer the fifth dose of the target drug weekly for at least about 4 weeks, followed by

[0123] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0124] or,

[0125] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0126] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0127] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0128] Administer a fourth dose of the target drug weekly for at least about 2 weeks, followed by

[0129] Administer the fifth dose of the target drug weekly for at least about 2 weeks, followed by

[0130] Administer the sixth dose of the target drug weekly for at least about 2 weeks, followed by

[0131] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks.

[0132] In some embodiments, the dosing regimen 1 or the first treatment period 1-3 comprises:

[0133] a) administer an initial dose of the target drug once weekly for at least about 4 weeks, followed by

[0134] d) administering a maintenance dose of the target drug once per week for at least about 4 weeks, e.g., about 20 weeks;

[0135] or,

[0136] a) administer an initial dose of the target drug once weekly for at least about 4 weeks, followed by

[0137] b) administering a second dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0138] d) administering a maintenance dose of the target drug once per week for at least about 4 weeks, e.g., about 16 weeks;

[0139] or,

[0140] a) administer an initial dose of the target drug once weekly for at least about 4 weeks, followed by

[0141] b) administering a second dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0142] c) administering a third dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0143] d) administering a maintenance dose of the target drug once per week for at least about 4 weeks, e.g., about 12 weeks;

[0144] or,

[0145] a) administer an initial dose of the target drug once weekly for at least about 4 weeks, followed by

[0146] b) administering a second dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0147] c) administering a third dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0148] Administer a fourth dose of the target drug weekly for at least about 4 weeks, followed by

[0149] Administer the fifth dose of the target drug weekly for at least about 4 weeks, followed by

[0150] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0151] or,

[0152] a) administer an initial dose of the target drug once weekly for at least about 4 weeks, followed by

[0153] b) administering a second dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0154] c) administering a third dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0155] Administer a fourth dose of the target drug weekly for at least about 4 weeks, followed by

[0156] Administer the fifth dose of the target drug weekly for at least about 4 weeks, followed by

[0157] Administer the sixth dose of the target drug weekly for at least about 4 weeks, followed by

[0158] d) administering a maintenance dose of the drug of interest once per week for at least about 4 weeks, such as about 12 weeks.

[0159] In some embodiments, the dosing regimen I or first treatment period I-1-1 comprises:

[0160] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0161] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 1 week;

[0162] or,

[0163] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0164] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0165] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0166] or,

[0167] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0168] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0169] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0170] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0171] or,

[0172] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0173] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0174] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0175] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0176] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0177] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0178] or,

[0179] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0180] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0181] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0182] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0183] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0184] About 6.0 mg to about 7.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0185] d) administering about 1.0 mg to about 8.0 mg of the drug of interest once per week for at least about 2 weeks.

[0186] In some embodiments, the dosing regimen I or the first treatment period I-2-1 comprises:

[0187] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0188] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0189] or,

[0190] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0191] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0192] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0193] or,

[0194] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0195] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0196] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0197] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0198] or,

[0199] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0200] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0201] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0202] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0203] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0204] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0205] or,

[0206] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0207] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0208] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0209] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0210] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0211] About 6.0 mg to about 7.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0212] d) administering about 1.0 mg to about 8.0 mg of the drug of interest once per week for at least about 4 weeks.

[0213] In some embodiments, the dosing regimen I or the first treatment period I-3-1 comprises:

[0214] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0215] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 20 weeks;

[0216] or,

[0217] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0218] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0219] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 16 weeks;

[0220] or,

[0221] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0222] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0223] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0224] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 12 weeks;

[0225] or,

[0226] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0227] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0228] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0229] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0230] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0231] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0232] or,

[0233] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0234] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0235] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0236] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0237] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0238] About 6.0 mg to about 7.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0239] d) administering about 1.0 mg to about 8.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks.

[0240] In some embodiments, the dosing regimen I or the first treatment period I-1-2 comprises:

[0241] a) administering about 0.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0242] d) administering about 1.0 mg of the drug of interest once a week for at least about 1 week;

[0243] or,

[0244] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week; thereafter

[0245] d) administering about 1.0 mg of the drug of interest once a week for at least about 1 week;

[0246] or,

[0247] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0248] d) administering about 2.0 mg of the drug of interest once a week for at least about 1 week;

[0249] or,

[0250] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0251] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0252] d) administering about 3.0 mg of the drug of interest once per week for at least about 2 weeks;

[0253] or,

[0254] a) administering about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0255] b) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0256] d) administering about 4.5 mg of the drug of interest once per week for at least about 2 weeks;

[0257] or,

[0258] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0259] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0260] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0261] d) administering about 4.5 mg of the drug of interest once per week for at least about 2 weeks;

[0262] or,

[0263] a) administering about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0264] b) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0265] c) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0266] d) administering about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0267] or,

[0268] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0269] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0270] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0271] d) administering about 4.0 mg of the drug of interest once per week for at least about 2 weeks;

[0272] or,

[0273] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0274] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0275] c) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0276] About 4.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0277] About 5.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0278] d) administering about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0279] or,

[0280] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0281] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0282] c) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0283] About 4.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0284] About 5.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0285] About 6.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0286] d) administering about 8.0 mg of the drug of interest once per week for at least about 2 weeks.

[0287] In some embodiments, the dosing regimen I or the first treatment period I-2-2 comprises:

[0288] a) administering about 0.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0289] d) administering about 1.0 mg of the drug of interest once per week for at least about 4 weeks;

[0290] or,

[0291] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0292] d) administering about 1.0 mg of the drug of interest once per week for at least about 4 weeks;

[0293] or,

[0294] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0295] d) administering about 2.0 mg of the drug of interest once per week for at least about 4 weeks;

[0296] or,

[0297] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0298] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0299] d) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks;

[0300] or,

[0301] a) administering about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0302] b) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0303] d) administering about 4.5 mg of the drug of interest once per week for at least about 4 weeks;

[0304] or,

[0305] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0306] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0307] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0308] d) administering about 4.5 mg of the drug of interest once per week for at least about 4 weeks;

[0309] or,

[0310] a) administering about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0311] b) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0312] c) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0313] d) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0314] or,

[0315] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0316] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0317] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0318] d) administering about 4.0 mg of the drug of interest once per week for at least about 4 weeks;

[0319] or,

[0320] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0321] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0322] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0323] About 4.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0324] About 5.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0325] d) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0326] or,

[0327] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0328] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0329] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0330] About 4.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0331] About 5.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0332] About 6.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0333] d) administering about 8.0 mg of the drug of interest once per week for at least about 4 weeks.

[0334] In some embodiments, the dosing regimen 1 or the first treatment period (1-3-2) comprises:

[0335] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks; thereafter

[0336] d) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 20 weeks;

[0337] or,

[0338] a) administering about 0.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0339] d) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 20 weeks;

[0340] or,

[0341] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0342] d) administering about 2.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 20 weeks;

[0343] or,

[0344] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0345] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0346] d) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 16 weeks;

[0347] or,

[0348] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0349] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0350] d) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks or about 16 weeks;

[0351] or,

[0352] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0353] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0354] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0355] d) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 12 weeks;

[0356] or,

[0357] a) administering about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0358] b) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0359] d) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 16 weeks;

[0360] or,

[0361] a) administering about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0362] b) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0363] c) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0364] d) administering about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 12 weeks;

[0365] or,

[0366] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0367] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0368] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0369] d) administering about 4.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 12 weeks;

[0370] or,

[0371] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0372] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0373] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0374] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0375] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0376] d) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0377] or,

[0378] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0379] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0380] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0381] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0382] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0383] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0384] d) administering about 8.0 mg of the drug of interest once per week for at least about 4 weeks, such as about 12 weeks.

[0385] In some embodiments, the dosing regimen I or first treatment period I-1-3 comprises:

[0386] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0387] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 1 week;

[0388] or,

[0389] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0390] b) administering about 1.0 mg to about 5.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0391] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 2 weeks;

[0392] or,

[0393] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0394] b) administering about 1.0 mg to about 5.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0395] c) administering about 1.0 mg to about 7.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0396] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 2 weeks;

[0397] or,

[0398] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0399] b) administering about 1.0 mg to about 4.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0400] c) administering about 1.0 mg to about 6.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0401] About 1.0 mg to about 8.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0402] About 1.0 mg to about 9.5 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0403] d) administering about 1.0 mg to about 11.0 mg of the drug of interest once per week for at least about 2 weeks;

[0404] or,

[0405] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0406] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0407] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0408] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0409] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0410] About 6.0 mg to about 7.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[0411] d) administering about 1.0 mg to about 8.0 mg of the drug of interest once per week for at least about 2 weeks.

[0412] In some embodiments, the dosing regimen I or the first treatment period I-2-3 comprises:

[0413] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0414] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 4 weeks;

[0415] or,

[0416] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0417] b) administering about 1.0 mg to about 5.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0418] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 4 weeks;

[0419] or,

[0420] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0421] b) administering about 1.0 mg to about 5.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0422] c) administering about 1.0 mg to about 7.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0423] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 4 weeks.

[0424] or,

[0425] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0426] b) administering about 1.0 mg to about 4.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0427] c) administering about 1.0 mg to about 6.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0428] About 1.0 mg to about 8.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0429] About 1.0 mg to about 9.5 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0430] d) administering about 1.0 mg to about 11.0 mg of the drug of interest once per week for at least about 4 weeks;

[0431] or,

[0432] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0433] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0434] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0435] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0436] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0437] About 6.0 mg to about 7.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0438] d) administering about 1.0 mg to about 8.0 mg of the drug of interest once per week for at least about 4 weeks.

[0439] In some embodiments, the dosing regimen I or the first treatment period I-3-3 comprises:

[0440] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0441] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 20 weeks;

[0442] or,

[0443] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0444] b) administering about 1.0 mg to about 5.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0445] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 16 weeks;

[0446] or,

[0447] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0448] b) administering about 1.0 mg to about 5.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0449] c) administering about 1.0 mg to about 7.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0450] d) administering about 0.5 mg to about 10.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 12 weeks;

[0451] or,

[0452] a) administering about 0.1 mg to about 2.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0453] b) administering about 1.0 mg to about 4.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0454] c) administering about 1.0 mg to about 6.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0455] About 1.0 mg to about 8.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0456] About 1.0 mg to about 9.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0457] d) administering about 1.0 mg to about 11.0 mg of the drug of interest once per week for at least about 4 weeks;

[0458] or,

[0459] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0460] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0461] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0462] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0463] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0464] About 6.0 mg to about 7.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0465] d) administering about 1.0 mg to about 8.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks.

[0466] Second treatment period

[0467] In some embodiments, the second treatment period comprises:

[0468] Administer a maintenance dose of the target drug once weekly for at least approximately 1 week;

[0469] or,

[0470] Administer a maintenance dose of the target drug every two weeks for at least approximately 2 weeks;

[0471] or,

[0472] Administer a maintenance dose of the target drug once weekly for at least approximately 1 week, followed by

[0473] Administer a maintenance dose of the target drug every two weeks for at least approximately 2 weeks;

[0474] or,

[0475] Administer a maintenance dose of the target drug once weekly for at least approximately 1 week, followed by

[0476] Administer the seventh dose of the target drug once weekly for at least about 1 week, followed by

[0477] The eighth dose of the drug of interest is administered once weekly for at least about 2 weeks.

[0478] In some embodiments, the maintenance dose is selected from about 0.5 mg to about 10.0 mg, about 3.0 mg to about 10.0 mg, about 1.0 mg to about 8.0 mg, about 1.0 mg to about 6.0 mg, about 1.0 mg to about 5.0 mg, about 3.0 mg to about 6.0 mg, about 4.0 mg to about 6.0 mg, or about 4.5 mg to about 6.0 mg. In some embodiments, the maintenance dose is selected from about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg , about 2.8mg, about 2.9mg, about 3.0mg, about 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4.0mg, about 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5.0mg, about 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, about 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, about 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg, about In some embodiments, the maintenance dose is selected from about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg, or about 8.0 mg.

[0479] In some embodiments, the seventh dose and the eighth dose are independently selected from about 0.5 mg to about 10.0 mg, about 3.0 mg to about 10.0 mg, about 1.0 mg to about 6.0 mg, about 1.0 mg to about 5.0 mg, about 1.0 mg to about 4.5 mg, about 1.0 mg to about 3.0 mg, about 2.0 mg to about 3.0 mg, about 3.0 mg to about 6.0 mg, or about 4.5 mg to about 6.0 mg. In some embodiments, the seventh dose, the eighth dose and the eighth dose are independently selected from about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg. g, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5 .2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, about 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, about 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg g, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10.0 mg; or any range between these point values. In some embodiments, the seventh dose and the eighth dose are independently selected from about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.5 mg or about 6.0 mg. In some embodiments, the seventh dose is about 2.0 mg. In some embodiments, the eighth dose is about 3.0 mg.

[0480] In some embodiments, a maintenance dose of the target drug is administered once per week for at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, etc. For example, the maintenance dose is administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 40 weeks, etc. In some embodiments, a maintenance dose of the target drug is administered once per week during the second treatment period for about 8 weeks, about 12 weeks, about 24 weeks, or about 28 weeks.

[0481] In some embodiments, a maintenance dose of the target drug is administered every 2 weeks for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, etc. For example, a maintenance dose is administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 40 weeks, etc. In some embodiments, a maintenance dose of the target drug is administered every 2 weeks for about 20 weeks.

[0482] In some embodiments, the seventh dose of the target drug is administered once per week for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 8 weeks, etc. For example, the ascending doses are administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, etc. In some embodiments, the seventh dose of the target drug is administered for about 4 weeks.

[0483] In some embodiments, the eighth dose of the target drug is administered once per week for at least about 2 weeks, at least about 4 weeks, at least about 6 weeks, at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 18 weeks, at least about 20 weeks, at least about 22 weeks, at least about 24 weeks, etc. For example, the eighth dose is administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 26 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 40 weeks, etc. In some embodiments, the eighth dose of the target drug is administered for about 16 weeks.

[0484] In some embodiments, the second treatment period II-1 comprises:

[0485] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0486] f) administering a maintenance dose of the target drug every two weeks for at least about 2 weeks;

[0487] or,

[0488] e) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0489] or,

[0490] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0491] g) administering a seventh dose of the drug of interest once weekly for at least about 1 week, followed by

[0492] h) administering the eighth dose of the drug of interest once per week for at least about 2 weeks.

[0493] In some embodiments, the second treatment period II-2 comprises:

[0494] e) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0495] f) administering a maintenance dose of the target drug every two weeks for at least about 4 weeks;

[0496] or,

[0497] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0498] or,

[0499] e) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0500] g) administering a seventh dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0501] h) administering the eighth dose of the drug of interest once per week for at least about 4 weeks.

[0502] In some embodiments, the second treatment period II-3 comprises:

[0503] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, such as about 8 weeks, followed by

[0504] f) administering a maintenance dose of the target drug once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0505] or,

[0506] e) administering a maintenance dose of the drug of interest once per week for at least about 4 weeks, e.g., about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, or about 28 weeks;

[0507] or,

[0508] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, such as about 8 weeks, followed by

[0509] g) administering a seventh dose of the drug of interest once a week for at least about 4 weeks, such as about 4 weeks, followed by

[0510] h) administering the eighth dose of the drug of interest once per week for at least about 4 weeks, e.g., about 16 weeks.

[0511] In some embodiments, the second treatment period II-1-1 comprises:

[0512] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0513] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0514] or,

[0515] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0516] or,

[0517] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0518] g) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0519] h) administering about 2.0 mg to about 3.0 mg of the drug of interest once per week for at least about 2 weeks.

[0520] In some embodiments, the second treatment period II-2-1 comprises:

[0521] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0522] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[0523] or,

[0524] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0525] or,

[0526] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0527] g) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0528] h) administering about 2.0 mg to about 3.0 mg of the drug of interest once per week for at least about 4 weeks.

[0529] In some embodiments, the second treatment period II-3-1 comprises:

[0530] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0531] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0532] or,

[0533] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks, e.g., about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, or about 28 weeks;

[0534] or,

[0535] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0536] g) administering about 2.0 mg to about 3.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0537] h) administering about 2.0 mg to about 3.0 mg of the drug of interest once per week for at least about 4 weeks, such as about 16 weeks.

[0538] In some embodiments, the second treatment period II-1-2 comprises:

[0539] e) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0540] f) administering about 3.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0541] or,

[0542] e) administering about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0543] f) administering about 4.5 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0544] or,

[0545] e) administering about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0546] f) administering about 6.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0547] or,

[0548] e) administering about 1.0 mg of the drug of interest once per week for at least about 2 weeks;

[0549] or,

[0550] e) administering about 2.0 mg of the drug of interest once per week for at least about 2 weeks;

[0551] or,

[0552] e) administering about 3.0 mg of the drug of interest once per week for at least about 2 weeks;

[0553] or,

[0554] e) administering about 4.0 mg of the drug of interest once per week for at least about 2 weeks;

[0555] or,

[0556] e) administering about 4.5 mg of the drug of interest once per week for at least about 2 weeks;

[0557] or,

[0558] e) administering about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0559] or,

[0560] e) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0561] g) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0562] h) administering about 3.0 mg of the drug of interest once per week for at least about 2 weeks.

[0563] In some embodiments, the second treatment period II-2-2 comprises:

[0564] e) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0565] f) administering about 3.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[0566] or,

[0567] e) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0568] f) administering about 4.5 mg of the drug of interest once every two weeks for at least about 4 weeks;

[0569] or,

[0570] e) administering about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0571] f) administering about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[0572] or,

[0573] e) administering about 1.0 mg of the drug of interest once per week for at least about 4 weeks;

[0574] or,

[0575] e) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks;

[0576] or,

[0577] e) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks;

[0578] or,

[0579] e) administering about 4.0 mg of the drug of interest once per week for at least about 2 weeks;

[0580] or,

[0581] e) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks;

[0582] or,

[0583] e) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0584] or,

[0585] e) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0586] g) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0587] h) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks.

[0588] In some embodiments, the second treatment period II-3-2 comprises:

[0589] e) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0590] f) administering about 3.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0591] or,

[0592] e) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0593] f) administering about 4.5 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0594] or,

[0595] e) administering about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0596] f) administering about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0597] or,

[0598] e) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks;

[0599] or,

[0600] e) administering about 2.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks, about 24 weeks, or about 28 weeks;

[0601] or,

[0602] e) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks or about 28 weeks;

[0603] or,

[0604] e) administering about 4.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 24 weeks or about 28 weeks;

[0605] or,

[0606] e) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks or about 28 weeks;

[0607] or,

[0608] e) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks, e.g., about 24 weeks or about 28 weeks;

[0609] or,

[0610] e) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0611] g) administering about 2.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0612] h) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks, such as about 16 weeks.

[0613] In some embodiments, the second treatment period II-1-3 comprises:

[0614] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0615] f) administering about 0.5 mg to about 10.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0616] or,

[0617] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 2 weeks;

[0618] or,

[0619] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0620] g) administering about 0.5 mg to about 10.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0621] h) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 2 weeks.

[0622] In some embodiments, the second treatment period II-2-3 comprises:

[0623] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0624] f) administering about 0.5 mg to about 10.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[0625] or,

[0626] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 4 weeks;

[0627] or,

[0628] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0629] g) administering about 0.5 mg to about 10.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0630] h) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 4 weeks.

[0631] In some embodiments, the second treatment period II-3-3 comprises:

[0632] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0633] f) administering about 0.5 mg to about 10.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0634] or,

[0635] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, or about 28 weeks;

[0636] or,

[0637] e) administering about 0.5 mg to about 10.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0638] g) administering about 0.5 mg to about 10.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0639] h) administering about 0.5 mg to about 10.0 mg of the drug of interest once per week for at least about 4 weeks, such as about 16 weeks.

[0640] Dosage regimen II

[0641] In some embodiments, the dosing regimen comprises:

[0642] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0643] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0644] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0645] g) administering a seventh dose of the drug of interest once weekly for at least about 1 week, followed by

[0646] h) administering an eighth dose of the target drug once per week for at least about 2 weeks;

[0647] or,

[0648] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0649] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0650] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0651] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0652] f) administering a maintenance dose of the target drug every two weeks for at least about 2 weeks;

[0653] or,

[0654] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0655] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0656] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0657] e) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0658] or,

[0659] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0660] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0661] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0662] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0663] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0664] f) administering a maintenance dose of the target drug every two weeks for at least about 2 weeks;

[0665] or,

[0666] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0667] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0668] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0669] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0670] e) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0671] or,

[0672] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0673] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0674] e) administering a maintenance dose of the target drug once weekly for at least about 1 week;

[0675] or,

[0676] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0677] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0678] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0679] Administer a fourth dose of the target drug weekly for at least about 2 weeks, followed by

[0680] Administer the fifth dose of the target drug weekly for at least about 2 weeks, followed by

[0681] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0682] e) administering a maintenance dose of the target medication once weekly for at least about 2 weeks.

[0683] In some embodiments, the dosing regimen comprises:

[0684] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0685] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0686] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0687] g) administering a seventh dose of the drug of interest once weekly for at least about 1 week, followed by

[0688] h) administering the eighth dose of the drug of interest once per week for at least about 2 weeks.

[0689] or,

[0690] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0691] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0692] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0693] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0694] f) administering a maintenance dose of the target drug every two weeks for at least about 2 weeks;

[0695] or,

[0696] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0697] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0698] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0699] e) administering a maintenance dose of the target medication once weekly for at least about 2 weeks.

[0700] or,

[0701] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0702] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0703] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0704] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0705] e) administer a maintenance dose of the target drug once weekly for at least about 1 week, followed by

[0706] f) administering a maintenance dose of the target drug every two weeks for at least about 2 weeks;

[0707] or,

[0708] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0709] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0710] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0711] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0712] e) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0713] or,

[0714] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0715] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0716] e) administering a maintenance dose of the target drug once weekly for at least about 2 weeks;

[0717] or,

[0718] a) administer an initial dose of the target drug once weekly for at least about 1 week, followed by

[0719] b) administering a second dose of the drug of interest once weekly for at least about 1 week, followed by

[0720] c) administering a third dose of the drug of interest once weekly for at least about 1 week, followed by

[0721] Administer a fourth dose of the target drug weekly for at least about 1 week, followed by

[0722] Administer the fifth dose of the target drug weekly for at least about 1 week, followed by

[0723] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0724] e) administering a maintenance dose of the target medication once weekly for at least about 2 weeks.

[0725] In some embodiments, the dosing regimen comprises:

[0726] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0727] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0728] e) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0729] g) administering a seventh dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0730] h) administering the eighth dose of the drug of interest once per week for at least about 4 weeks.

[0731] or,

[0732] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0733] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0734] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0735] e) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0736] f) administering a maintenance dose of the target drug every two weeks for at least about 4 weeks;

[0737] or,

[0738] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0739] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0740] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0741] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0742] or,

[0743] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0744] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0745] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0746] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0747] e) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0748] f) administering a maintenance dose of the target medication every two weeks for at least about 4 weeks.

[0749] or,

[0750] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0751] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0752] c) administering a third dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0753] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0754] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0755] or,

[0756] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0757] d) administer a maintenance dose of the target drug once weekly for at least about 2 weeks, followed by

[0758] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks;

[0759] or,

[0760] a) administer an initial dose of the target drug once weekly for at least about 2 weeks, followed by

[0761] b) administering a second dose of the drug of interest once weekly for at least about 2 weeks, followed by

[0762] c) administering a third dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0763] Administer a fourth dose of the target drug weekly for at least about 4 weeks, followed by

[0764] Administer the fifth dose of the target drug weekly for at least about 4 weeks, followed by

[0765] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0766] e) administering a maintenance dose of the target medication once weekly for at least about 4 weeks.

[0767] In some embodiments, the dosing regimen comprises:

[0768] a) administering an initial dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0769] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, e.g., about 20 weeks, followed by

[0770] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, such as about 8 weeks, followed by

[0771] g) administering a seventh dose of the drug of interest once a week for at least about 4 weeks, such as about 4 weeks, followed by

[0772] h) administering an eighth dose of the drug of interest once per week for at least about 4 weeks, e.g., about 16 weeks;

[0773] or,

[0774] a) administering an initial dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0775] b) administering a second dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0776] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, e.g., about 16 weeks, followed by

[0777] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, such as about 8 weeks, followed by

[0778] f) administering a maintenance dose of the target drug once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0779] or,

[0780] a) administering an initial dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0781] b) administering a second dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0782] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, e.g., about 16 weeks, followed by

[0783] e) administering a maintenance dose of the drug of interest once per week for at least about 4 weeks, such as about 8 weeks or about 28 weeks.

[0784] or,

[0785] a) administering an initial dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0786] b) administering a second dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0787] c) administering a third dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0788] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, such as about 12 weeks, followed by

[0789] e) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, such as about 8 weeks, followed by

[0790] f) administering a maintenance dose of the target drug once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0791] or,

[0792] a) administering an initial dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0793] b) administering a second dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0794] c) administering a third dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0795] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, such as about 12 weeks, followed by

[0796] e) administering a maintenance dose of the drug of interest once per week for at least about 4 weeks, e.g., about 24 weeks or about 28 weeks;

[0797] or,

[0798] a) administering an initial dose of the drug of interest once a week for at least about 4 weeks, e.g., about 4 weeks, followed by

[0799] d) administering a maintenance dose of the target drug once weekly for at least about 4 weeks, e.g., about 20 weeks, followed by

[0800] e) administering a maintenance dose of the drug of interest once per week for at least about 4 weeks, e.g., about 8 weeks, about 24 weeks, or about 28 weeks;

[0801] or,

[0802] a) administer an initial dose of the target drug once weekly for at least about 4 weeks, followed by

[0803] b) administering a second dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0804] c) administering a third dose of the drug of interest once weekly for at least about 4 weeks, followed by

[0805] Administer a fourth dose of the target drug weekly for at least about 4 weeks, followed by

[0806] Administer the fifth dose of the target drug weekly for at least about 4 weeks, followed by

[0807] d) administer a maintenance dose of the target drug once weekly for at least about 4 weeks, followed by

[0808] e) administering a maintenance dose of the drug of interest once per week for at least about 4 weeks, such as about 24 weeks.

[0809] In some embodiments, the dosing regimen comprises:

[0810] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0811] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0812] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0813] g) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0814] h) administering about 2.0 mg to about 3.0 mg of the drug of interest once per week for at least about 2 weeks;

[0815] or,

[0816] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0817] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0818] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0819] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0820] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0821] or,

[0822] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0823] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0824] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0825] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0826] or,

[0827] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0828] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0829] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0830] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0831] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0832] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0833] or,

[0834] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0835] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0836] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0837] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0838] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0839] or,

[0840] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0841] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0842] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0843] or,

[0844] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0845] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0846] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0847] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0848] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[0849] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0850] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks.

[0851] In some embodiments, the dosing regimen comprises:

[0852] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0853] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0854] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0855] g) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0856] h) administering about 2.0 mg to about 3.0 mg of the drug of interest once per week for at least about 4 weeks;

[0857] or,

[0858] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0859] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0860] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0861] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0862] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[0863] or,

[0864] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0865] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0866] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0867] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0868] or,

[0869] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0870] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0871] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0872] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0873] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0874] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[0875] or,

[0876] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0877] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0878] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0879] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0880] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0881] or,

[0882] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0883] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0884] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[0885] or,

[0886] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0887] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0888] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0889] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0890] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0891] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0892] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks.

[0893] In some embodiments, the dosing regimen comprises:

[0894] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0895] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 20 weeks, followed by

[0896] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0897] g) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0898] h) administering about 2.0 mg to about 3.0 mg of the drug of interest once per week for at least about 4 weeks, e.g., about 16 weeks;

[0899] or,

[0900] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0901] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0902] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 16 weeks, followed by

[0903] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0904] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0905] or,

[0906] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0907] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0908] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0909] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks, followed by

[0910] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[0911] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[0912] or,

[0913] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0914] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0915] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0916] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks, followed by

[0917] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks, e.g., about 24 weeks or about 28 weeks;

[0918] or,

[0919] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0920] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 16 weeks or about 20 weeks, followed by

[0921] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks, about 24 weeks, or about 28 weeks;

[0922] or,

[0923] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0924] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0925] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 16 weeks, followed by

[0926] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks, e.g., about 8 weeks or 28 weeks;

[0927] or,

[0928] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0929] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0930] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0931] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0932] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[0933] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[0934] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 4 weeks, such as about 24 weeks.

[0935] In some embodiments, the dosing regimen comprises:

[0936] a) administering about 0.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0937] d) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0938] e) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0939] g) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0940] h) administering about 3.0 mg of the drug of interest once per week for at least about 2 weeks.

[0941] or,

[0942] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0943] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0944] d) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0945] e) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0946] f) administering about 3.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0947] or,

[0948] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0949] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0950] d) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0951] e) administering about 3.0 mg of the drug of interest once per week for at least about 2 weeks;

[0952] or,

[0953] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0954] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0955] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0956] d) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0957] e) administering about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0958] f) administering about 4.5 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0959] or,

[0960] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0961] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0962] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0963] d) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0964] e) administering about 4.5 mg of the drug of interest once per week for at least about 2 weeks;

[0965] or,

[0966] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0967] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0968] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0969] d) administering about 4.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0970] e) administering about 4.0 mg of the drug of interest once per week for at least about 2 weeks.

[0971] or,

[0972] a) administering about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0973] b) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0974] c) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0975] d) administering about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0976] e) administering about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0977] f) administering about 6.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[0978] or,

[0979] a) administering about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0980] b) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0981] c) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0982] d) administering about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0983] e) administering about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[0984] or

[0985] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0986] d) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0987] e) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, and thereafter;

[0988] or

[0989] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0990] d) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0991] e) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, and thereafter;

[0992] or

[0993] a) administering about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[0994] b) administering about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0995] d) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[0996] e) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, and thereafter;

[0997] or,

[0998] a) administering about 1.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[0999] b) administering about 2.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1000] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1001] About 4.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[1002] About 5.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[1003] d) administering about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1004] e) administering about 6.0 mg of the drug of interest once per week for at least about 2 weeks.

[1005] In some embodiments, the dosing regimen comprises:

[1006] a) administering about 0.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1007] d) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1008] e) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1009] g) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1010] h) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks;

[1011] or,

[1012] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1013] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1014] d) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1015] e) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1016] f) administering about 3.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[1017] or,

[1018] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1019] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1020] d) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1021] e) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks;

[1022] or,

[1023] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1024] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1025] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1026] d) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1027] e) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1028] f) administering about 4.5 mg of the drug of interest once every two weeks for at least about 4 weeks;

[1029] or,

[1030] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1031] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1032] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1033] d) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1034] e) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks;

[1035] or,

[1036] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1037] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1038] c) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1039] d) administering about 4.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1040] e) administering about 4.0 mg of the drug of interest once per week for at least about 4 weeks;

[1041] or,

[1042] a) administering about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1043] b) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1044] c) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1045] d) administering about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1046] e) administering about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1047] f) administering about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[1048] or,

[1049] a) administering about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1050] b) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1051] c) administering about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1052] d) administering about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1053] e) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks;

[1054] or

[1055] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1056] d) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1057] e) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, and thereafter;

[1058] or

[1059] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1060] d) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1061] e) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, and thereafter;

[1062] or

[1063] a) administering about 1.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1064] b) administering about 3.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1065] d) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1066] e) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, and thereafter;

[1067] or,

[1068] a) administering about 1.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1069] b) administering about 2.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1070] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1071] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1072] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1073] d) administering about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1074] e) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks.

[1075] In some embodiments, the dosing regimen comprises:

[1076] a) administering about 0.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1077] d) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 20 weeks, followed by

[1078] e) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[1079] g) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1080] h) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks, e.g., about 16 weeks;

[1081] or,

[1082] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1083] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1084] d) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 16 weeks, followed by

[1085] e) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[1086] f) administering about 3.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[1087] or,

[1088] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1089] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1090] d) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 16 weeks, followed by

[1091] e) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks or about 28 weeks;

[1092] or,

[1093] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1094] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1095] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1096] d) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks, followed by

[1097] e) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[1098] f) administering about 4.5 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., at least about 20 weeks;

[1099] or,

[1100] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1101] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1102] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1103] d) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks, followed by

[1104] e) administering about 4.5 mg of the drug of interest once per week for at least about 4 weeks, such as about 28 weeks.

[1105] or,

[1106] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1107] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1108] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1109] d) administering about 4.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks, followed by

[1110] e) administering about 4.0 mg of the drug of interest once per week for at least about 4 weeks, e.g., about 24 or about 28 weeks;

[1111] or,

[1112] a) administering about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1113] b) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1114] c) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1115] d) administering about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks, followed by

[1116] e) administering about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, followed by

[1117] f) administering about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks, e.g., about 20 weeks;

[1118] or,

[1119] a) administering about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1120] b) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1121] c) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1122] d) administering about 6.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks, followed by

[1123] e) administering about 6.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 28 weeks;

[1124] or

[1125] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1126] d) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 20 weeks, followed by

[1127] e) administering about 1.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 8 weeks, and thereafter;

[1128] or

[1129] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1130] d) administering about 2.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 20 weeks, followed by

[1131] e) administering about 2.0 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks, about 24 weeks, or about 28 weeks;

[1132] or

[1133] a) administering about 1.5 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1134] b) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1135] d) administering about 4.5 mg of the drug of interest once weekly for at least about 4 weeks, e.g., about 16 weeks, followed by

[1136] e) administering about 4.5 mg of the drug of interest once a week for at least about 4 weeks, e.g., about 8 weeks;

[1137] or,

[1138] a) administering about 1.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1139] b) administering about 2.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1140] c) administering about 3.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1141] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1142] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1143] d) administering about 6.0 mg of the drug of interest once weekly for at least about 4 weeks, followed by

[1144] e) administering about 6.0 mg of the drug of interest once per week for at least about 4 weeks, such as about 24 weeks.

[1145] In some embodiments, the present disclosure provides another administration method, wherein the maintenance dose of the target drug is 0.5 mg-10.0 mg, 1.0 mg-8.0 mg, 1.0 mg-6.0 mg or 1.0 mg-5.0 mg; for example, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg or about 8.0 mg.

[1146] In some embodiments, the drug of interest is administered in a dose-escalating manner or a dose-titration manner.

[1147] In some embodiments, the target drug administration frequency is once a week.

[1148] In some embodiments, the target drug is administered starting with an initial dose, with the dose increased approximately every 4 weeks, with a dose increment of 1 mg to 2 mg (e.g., one or more selected from about 0.5 mg, about 1 mg, about 1.5 mg, and about 2.0 mg), and gradually titrated to the maintenance dose of the target drug.

[1149] In some embodiments, the initial dose is about 0.1 mg to about 2.5 mg, for example, the initial dose is about 0.5 mg, about 1.0 mg, or about 1.5 mg.

[1150] In some embodiments, the initial dose of the target drug is about 0.5 mg, about 1.0 mg, or about 1.5 mg, which is administered for at least about 4 weeks; the dose is then increased approximately every 4 weeks, with the dose increment being selected from one or more of about 0.5 mg, about 1 mg, about 1.5 mg, and about 2.0 mg, and gradually titrated to a maintenance dose of the target drug of 1.0 mg-8.0 mg (e.g., about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg, or about 8.0 mg).

[1151] In some embodiments, the target drug is dose-increased approximately every 4 weeks, and each dose increase is an increase in the dose based on the previous dose, for example, an increase of 1 mg to 2 mg based on the previous dose, for example, an increase of about 0.5 mg, about 1 mg, about 1.5 mg, or about 2.0 mg based on the previous dose. In some embodiments, the magnitude of each dose increase is the same or different. For example, the initial dose is about 1 mg, the second dose is about 2 mg, the dose increase is about 1 mg, the third dose is about 3 mg, the dose increase is about 1 mg, and the maintenance dose is 4.5 mg with a dose increase of about 1.5 mg; for example, the initial dose is about 1 mg, the second dose is about 2 mg, the dose increase is about 1 mg, the third dose is about 3 mg, the dose increase is about 1 mg, and the maintenance dose is 4 mg with a dose increase of about 1 mg.

[1152] In some embodiments, the maintenance dose is administered once a week.

[1153] In some embodiments, the maintenance dose is administered once every two weeks.

[1154] In some embodiments, the maintenance dose is administered once a week and then once every two weeks, for example, the maintenance dose is administered once a week for at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks, and then the maintenance dose is administered once every two weeks.

[1155] In any of the dosing regimens disclosed herein, the dosage and duration of administration may be adjusted based on the subject's tolerance, the desired preventive or therapeutic results, or other circumstances determined by a physician or health care provider.

[1156] <Target drug>

[1157] In some embodiments, the target drug is selected from a GLP-1 analogue or a pharmaceutically acceptable salt thereof.

[1158] In some embodiments, the GLP-1 analog has agonist activity at at least one of the following receptors: a GLP-1 receptor, a GIP receptor. In some embodiments, the GLP-1 analog has agonist activity at both a GLP-1 receptor and a GIP receptor.

[1159] In some embodiments, the GLP-1 analog is a dual agonist of the GLP-1 receptor and the GIP receptor.

[1160] In some embodiments, the GLP-1 analogue is a GLP-1 analogue comprising or represented by the following structure, or a pharmaceutically acceptable salt thereof:

[1161] H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGGPSSGAPPPS-NH2.

[1162] In some embodiments, the K(OEG-OEG-γGlu-C20-OH) has the following structure:

[1163] In some embodiments, the K(OEG-OEG-γGlu-C20-OH) has the following structure:

[1164] In some embodiments, the target drug is a GLP-1 analogue comprising the structure shown below, or a pharmaceutically acceptable salt thereof,

[1165] In some embodiments, the target drug is selected from any GLP-1 analogue or pharmaceutically acceptable salt thereof, or composition disclosed in WO2021239082A1. The present disclosure incorporates the structures, preparation methods, and other related contents of the GLP-1 analogue or pharmaceutically acceptable salt thereof in the above-mentioned patents into the present disclosure by reference.

[1166] In some embodiments, the target drug is an acetate or sodium salt of a GLP-1 analogue comprising the structure shown below,

[1167] In some embodiments, the GLP-1 analog is telpotide or a pharmaceutically acceptable salt thereof.

[1168] In some embodiments, the GLP-1 analog is a compound represented by any of the following structures or a pharmaceutically acceptable salt thereof:

[1169] <Obese or overweight>

[1170] In some embodiments, the present disclosure provides a method for improving weight management in a subject in need thereof, comprising administering to a subject in need thereof a target drug according to the dosing regimen of the present disclosure, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof as shown in the following structure:

[1171] H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGGPSSGAPPPS-NH2.

[1172] In some embodiments, the present disclosure provides a method for treating obesity, comprising administering a target drug to a subject in need thereof according to the dosing regimen of the present disclosure, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof as shown in the following structure:

[1173] H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGGPSSGAPPPS-NH2.

[1174] In some embodiments, the present disclosure provides a target drug for treating obesity, comprising administering the target drug to a subject in need thereof according to the dosing regimen of the present disclosure, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof as shown in the following structure:

[1175] H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGGPSSGAPPPS-NH2.

[1176] In some embodiments, the K(OEG-OEG-γGlu-C20-OH) has the following structure:

[1177] In some embodiments, the K(OEG-OEG-γGlu-C20-OH) has the following structure:

[1178] In some embodiments, the target drug is a GLP-1 analogue comprising the structure shown below or a pharmaceutically acceptable salt thereof,

[1179] In some embodiments, the subject is administered the target drug to a subject in need thereof according to any of the aforementioned dosing regimens.

[1180] In some embodiments, the subject is obese or overweight.

[1181] In some embodiments, the subject is obese or overweight and has at least one weight-related comorbidity. In some embodiments, the comorbidity includes one or more of prediabetes, hypertension, and dyslipidemia.

[1182] In some embodiments, the subject has a BMI ≥ 28.0 kg / m 2 and / or a BMI ≤ 40.0 kg / m 2 .

[1183] In some embodiments, the subject has a BMI ≥ 24.0 kg / m2 and / or a BMI < 28.0 kg / m 2 , and has at least one weight-related comorbidity. In some embodiments, the comorbidity includes one or more of prediabetes, hypertension, and dyslipidemia.

[1184] In some embodiments, the prediabetic subjects include impaired fasting glucose, impaired glucose tolerance, and a mixed state of both.

[1185] In some embodiments, the prediabetic subjects are those with a fasting blood glucose of 6.1 mmol / L < fasting blood glucose < 7.0 mmol / L, or those with an HbAlc of 5.7% < HbAlc < 6.5%.

[1186] In some embodiments, the method reduces the weight of the subject.

[1187] In some embodiments, the maintenance dose of the target drug is 0.5 mg - 10.0 mg, 1.0 mg - 8.0 mg, or 1.0 mg - 5.0 mg; for example, it is about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg, or about 8.0 mg.

[1188] In some embodiments, the target drug is administered in a dose-escalating manner or a dose-titrating manner.

[1189] In some embodiments, the dosing frequency of the target drug is once a week and / or once every two weeks. In some embodiments, the target drug is administered starting from the initial dose, with the dose increasing approximately once every 4 weeks, and the dose escalation range is 1 mg - 2 mg (for example, selected from one or more of about 0.5 mg, about 1 mg, about 1.5 mg, and about 2.0 mg), and gradually titrated to the maintenance dose of the target drug.

[1190] In some embodiments, the initial dose is about 0.1 mg to about 2.5 mg. For example, the initial dose is about 0.5 mg, about 1.0 mg, or about 1.5 mg.

[1191] In some embodiments, the initial dose of the target drug is about 0.5 mg, about 1.0 mg, or about 1.5 mg, which is administered for at least about 4 weeks; the dose is then increased approximately every 4 weeks, with the dose increment being selected from one or more of about 0.5 mg, about 1 mg, about 1.5 mg, and about 2.0 mg, gradually titrated to a maintenance dose of the target drug of 1.0 mg-8.0 mg (e.g., about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg, or about 8.0 mg).

[1192] In some embodiments, the target drug is dose-escalated approximately every four weeks, with each dose increase being an increase in the dose based on the previous dose, for example, an increase of 1 mg to 2 mg based on the previous dose, for example, an increase of about 0.5 mg, about 1 mg, about 1.5 mg, or about 2.0 mg based on the previous dose. In some embodiments, the magnitude of each dose increase is the same or different. For example, the initial dose is about 1 mg, the second dose is about 2 mg, the dose increase is about 1 mg, the third dose is about 3 mg, the dose increase is about 1 mg, and the maintenance dose is 4.5 mg, with a dose increase of about 0.5 mg; for example, the initial dose is about 1 mg, the second dose is about 2 mg, the dose increase is about 1 mg, the third dose is about 3 mg, the dose increase is about 1 mg, and the maintenance dose is 4 mg, with a dose increase of about 1 mg.

[1193] In some embodiments, the maintenance dose is administered once a week.

[1194] In some embodiments, the maintenance dose is administered once every two weeks.

[1195] In some embodiments, the maintenance dose is administered once a week and then once every two weeks, for example, the maintenance dose is administered once a week for at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks, and then the maintenance dose is administered once every two weeks.

[1196] In some embodiments, the dosing regimen includes any of the following:

[1197] (1)

[1198] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1199] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1200] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1201] g) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1202] h) administering about 2.0 mg to about 3.0 mg of the drug of interest once per week for at least about 2 weeks;

[1203] (2)

[1204] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1205] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1206] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1207] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1208] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[1209] (3)

[1210] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1211] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1212] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1213] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[1214] (4)

[1215] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1216] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1217] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1218] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1219] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1220] f) administering about 1.0 mg to about 6.0 mg of the drug of interest once every two weeks for at least about 2 weeks;

[1221] (5)

[1222] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1223] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1224] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1225] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1226] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[1227] (6)

[1228] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1229] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1230] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks;

[1231] (7)

[1232] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1233] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1234] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1235] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[1236] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[1237] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1238] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once per week for at least about 2 weeks; or,

[1239] (8)

[1240] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1241] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1242] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1243] About 4.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[1244] About 5.0 mg to about 6.0 mg of the target drug is administered once weekly for at least about 1 week, followed by

[1245] About 6.0 mg to about 7.0 mg of the target drug is administered once weekly for at least about 2 weeks, followed by

[1246] d) administering about 1.0 mg to about 8.0 mg of the drug of interest once per week for at least about 4 weeks.

[1247] In some embodiments, the dosing regimen comprises any of the following:

[1248] (1) administering about 0.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1249] About 1.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1250] About 1.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1251] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1252] administering about 3.0 mg of the target drug once weekly for at least about 4 weeks;

[1253] (2) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1254] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1255] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1256] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1257] administering about 3.0 mg of the target drug once every two weeks for at least about 4 weeks;

[1258] (3) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1259] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1260] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1261] administering about 3.0 mg of the target drug once weekly for at least about 4 weeks;

[1262] (4) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1263] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1264] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1265] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1266] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1267] administering about 4.5 mg of the target drug once every two weeks for at least about 4 weeks;

[1268] (5) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1269] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1270] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1271] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1272] administering about 4.5 mg of the target drug once weekly for at least about 4 weeks;

[1273] (6) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1274] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1275] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1276] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1277] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1278] administering about 6.0 mg of the target drug once every two weeks for at least about 4 weeks;

[1279] (7) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1280] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1281] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1282] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1283] administering about 6.0 mg of the target drug once weekly for at least about 4 weeks;

[1284] (8) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1285] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1286] administering about 2.0 mg of the target drug once weekly for at least about 4 weeks;

[1287] (9) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1288] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1289] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1290] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1291] administering about 4.0 mg of the target drug once weekly for at least about 4 weeks;

[1292] (10) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1293] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1294] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1295] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1296] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1297] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1298] administering about 6.0 mg of the target drug once weekly for at least about 4 weeks; or,

[1299] (11) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1300] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1301] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1302] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1303] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1304] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1305] About 8.0 mg of the drug of interest is administered once per week for at least about 4 weeks.

[1306] In some embodiments, the dosing regimen comprises any of the following:

[1307] (1) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1308] administering about 0.5 mg to about 10.0 mg of the target drug once a week for at least about 4 weeks, for example, about 28 weeks;

[1309] Optionally, about 2.0 mg to about 3.0 mg of the drug of interest is administered once weekly for at least about 4 weeks, followed by

[1310] administering about 2.0 mg to about 3.0 mg of the target drug once a week for at least about 4 weeks, for example, about 16 weeks;

[1311] (2) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1312] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1313] administering about 0.5 mg to about 10.0 mg of the target drug once a week for at least about 4 weeks, for example, about 24 weeks;

[1314] Optionally, about 0.5 mg to about 10.0 mg of the target drug is then administered once every two weeks for at least about 4 weeks, such as about 20 weeks;

[1315] (3) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1316] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1317] About 1.0 mg to about 7.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1318] administering about 0.5 mg to about 10.0 mg of the target drug once a week for at least about 4 weeks, for example, about 20 weeks;

[1319] Optionally, about 0.5 mg to about 10.0 mg of the target drug is then administered once every two weeks for at least about 4 weeks, such as about 20 weeks;

[1320] (4) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1321] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1322] About 1.0 mg to about 7.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1323] About 1.0 mg to about 9 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1324] About 1.0 mg to about 11 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1325] administering about 0.5 mg to about 10.0 mg of the target drug once a week for at least about 4 weeks, such as about 24 weeks; or,

[1326] (5) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1327] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1328] About 1.0 mg to about 7.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1329] About 1.0 mg to about 9 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1330] About 1.0 mg to about 11 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1331] About 1.0 mg to about 11 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1332] administering about 0.5 mg to about 10.0 mg of the target drug once a week for at least about 4 weeks, for example, about 12 weeks;

[1333] (6) administering about 0.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1334] administering about 1.0 mg of the target drug once a week for at least about 4 weeks, for example, about 28 weeks;

[1335] Optionally, about 2.0 mg of the drug of interest is administered once weekly for at least about 4 weeks, followed by

[1336] About 3.0 mg of the drug of interest is administered once a week for at least about 4 weeks, such as about 16 weeks.

[1337] (7) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1338] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1339] administering about 3.0 mg of the target drug once a week for at least about 4 weeks, for example, about 24 weeks;

[1340] Optionally, about 3.0 mg of the target drug is subsequently administered once every two weeks for at least about 4 weeks, such as about 20 weeks;

[1341] (8) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1342] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1343] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1344] administering about 4.5 mg of the target drug once a week for at least about 4 weeks, for example, about 20 weeks,

[1345] Optionally, about 4.5 mg of the target drug is subsequently administered once every two weeks for at least about 4 weeks, such as about 20 weeks;

[1346] (9) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1347] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1348] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1349] administering about 6.0 mg of the target drug once a week for at least about 4 weeks, for example, about 20 weeks,

[1350] Optionally, about 6.0 mg of the target drug is subsequently administered once every two weeks for at least about 4 weeks, such as about 20 weeks;

[1351] (10) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1352] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1353] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1354] administering about 4.0 mg of the target drug once a week for at least about 4 weeks, for example, about 32 weeks;

[1355] (11) Administer approximately 1.0 mg of the target drug once a week for approximately 4 weeks, followed by

[1356] administering about 2.0 mg of the target drug once a week for at least about 4 weeks, for example, about 44 weeks;

[1357] (12) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1358] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1359] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1360] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1361] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1362] administering about 6.0 mg of the target drug once a week for at least about 4 weeks, such as about 28 weeks; or,

[1363] (13) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1364] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1365] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1366] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1367] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1368] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1369] About 8.0 mg of the drug of interest is administered once a week for at least about 4 weeks, such as about 12 weeks.

[1370] In some embodiments, the method improves or reduces any of the following indicators in the subject:

[1371] 1) Carbohydrate metabolism, such as fasting plasma glucose, fasting serum insulin, insulin resistance (HOMA model), and glycated hemoglobin HbA1c;

[1372] 2) Blood lipids, such as total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG).

[1373] In some embodiments, the methods of improving or decreasing are relative to a baseline.

[1374] In some embodiments, the subject's body weight is reduced by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% compared to baseline following administration according to the disclosed dosing methods.

[1375] In some embodiments, the subject's systolic blood pressure is reduced by at least 4 mmHg or at least 8 mmHg following administration according to the disclosed dosing methods, compared to baseline.

[1376] In some embodiments, the subject's waist circumference is reduced by at least 5 cm, at least 10 cm, or at least 15 cm following administration according to the disclosed dosing methods, compared to baseline.

[1377] Diabetes

[1378] In some embodiments, the present disclosure provides a method for treating type 2 diabetes, comprising administering a target drug to a subject in need thereof according to the dosing regimen of the present disclosure, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof as shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1379] In some embodiments, the present disclosure provides a method for improving weight control in subjects with type 2 diabetes, comprising administering a target drug to a subject in need thereof according to the above-mentioned dosing regimen, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof as shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1380] In some embodiments, the present disclosure provides a method for improving glycemic control in subjects with type 2 diabetes, comprising administering a target drug to a subject in need thereof according to the above-mentioned dosing regimen, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof as shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1381] In some embodiments, the present disclosure provides a method for improving blood lipid control in subjects with type 2 diabetes, comprising administering a target drug to a subject in need thereof according to the above-mentioned dosing regimen, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof as shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1382] In some embodiments, the present disclosure provides a method for improving blood pressure (such as hypertension) in a subject with type 2 diabetes, comprising administering a target drug to a subject in need thereof according to the above-mentioned dosing regimen, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1383] In some embodiments, the present disclosure provides a use of a target drug in combination with other hypoglycemic drugs in the preparation of a drug for treating type 2 diabetes, wherein the other hypoglycemic drug is metformin, or metformin and an SGLT2 inhibitor, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1384] In some embodiments, the present disclosure provides the following target drug for treating a subject with type 2 diabetes; wherein the subject is also receiving treatment with other hypoglycemic drugs, and the other hypoglycemic drugs are metformin, or metformin and an SGLT2 inhibitor, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1385] In some embodiments, the present disclosure provides the following target drug in combination with other hypoglycemic drugs for the treatment of type 2 diabetes, wherein the other hypoglycemic drug is metformin, or metformin and an SGLT2 inhibitor. For example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1386] In some embodiments, the present disclosure provides a pharmaceutical composition for treating type 2 diabetes, comprising an effective therapeutic amount of the above-mentioned target drug and other hypoglycemic drugs, wherein the other hypoglycemic drugs are metformin, or metformin and an SGLT2 inhibitor, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1387] In some embodiments, the present disclosure provides a kit or product for treating type 2 diabetes, comprising an effective therapeutic amount of the above-mentioned target drug and other hypoglycemic drugs, wherein the other hypoglycemic drugs are metformin, or metformin and an SGLT2 inhibitor, for example, the target drug comprises or is a GLP-1 analogue or a pharmaceutically acceptable salt thereof shown in the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1388] In some embodiments, the K(OEG-OEG-γGlu-C20-OH) has the following structure:

[1389] In some embodiments, the K(OEG-OEG-γGlu-C20-OH) has the following structure:

[1390] In some embodiments, the target drug is a GLP-1 analogue comprising the structure shown below or a pharmaceutically acceptable salt thereof,

[1391] In some embodiments, the target drug is an acetate or sodium salt of a GLP-1 analogue comprising the structure shown below,

[1392] In some embodiments, the subject with type 2 diabetes has an HbA1c ≥ 7.5% and / or an HbA1c ≤ 11%.

[1393] In some embodiments, the type 2 diabetes subject is one for whom lifestyle intervention alone (e.g., diet and / or exercise control) remains ineffective, for example, poor glycemic control remains despite lifestyle intervention alone, or for example, one for whom the target HbA1c cannot be achieved after lifestyle intervention alone. In some embodiments, the type 2 diabetes subject is one for whom HbA1c remains greater than 7% after lifestyle intervention alone, for example, HbA1c ≥ 7.5%.

[1394] In some embodiments, the subject with type 2 diabetes is one who is still experiencing poor results with metformin treatment, e.g., one who is still experiencing poor glycemic control with metformin treatment, e.g., one who is unable to achieve target HbA1c with metformin treatment. In some embodiments, the subject has an HbA1c > 7% after metformin treatment, e.g., an HbA1c ≥ 7.5%.

[1395] In some embodiments, the subject with type 2 diabetes is one who has not responded well to metformin combined with an SGLT2 inhibitor, for example, one who has not achieved adequate glycemic control despite treatment with metformin combined with an SGLT2 inhibitor, or one who has not been able to achieve target HbA1c despite treatment with metformin combined with an SGLT2 inhibitor. In some embodiments, the subject has an HbA1c > 7% after treatment with metformin combined with an SGLT2 inhibitor, for example, an HbA1c ≥ 7.5%.

[1396] In some embodiments, the subject receiving the drug of interest is also administered metformin.

[1397] In some embodiments, the subject receiving the target drug is also receiving stable metformin.

[1398] In some embodiments, the subject receiving the drug of interest is also administered metformin and an SGLT2 inhibitor.

[1399] In some embodiments, the subject receiving the target drug is also receiving stable treatment with metformin and an SGLT2 inhibitor.

[1400] In some embodiments, stable treatment is defined as receiving the target drug before treatment (metformin and SGLT2 inhibitor) and the total daily dose has not changed, for example, the metformin dose is ≥1500 mg / day or the maximum tolerated dose (≥1000 mg / day); the SGLT2 inhibitor dose is the daily dose recommended in the instructions.

[1401] In some embodiments, the subject has a BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[1402] In some embodiments, the subject is obese.

[1403] In some embodiments, the subject is non-obese.

[1404] In some embodiments, the subject with type 2 diabetes is at least one of the following:

[1405] 1) Patients whose disease is poorly controlled by lifestyle intervention alone (such as diet and / or exercise control) or metformin;

[1406] 2) HbA1c ≥ 7.5% and / or HbA1c ≤ 10.5%;

[1407] 3) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[1408] In some embodiments, the subject with type 2 diabetes is at least one of the following:

[1409] 1) Patients whose blood sugar is still poorly controlled despite treatment with metformin or metformin combined with SGLT2 inhibitors;

[1410] 2) HbA1c ≥ 7.5% and / or HbA1c ≤ 11%;

[1411] 3) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[1412] In some embodiments, the diabetic subject is at least one of the following:

[1413] 1) Currently taking metformin or metformin combined with SGLT2 inhibitors;

[1414] 2) HbA1c ≥ 7.5% and / or HbA1c ≤ 11%;

[1415] 3) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[1416] In some embodiments, the target drug maintenance dose is 0.5 mg-10.0 mg, 1.0 mg-6.0 mg, or 1.0 mg-5.0 mg; for example, about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, or about 4.5 mg. In some embodiments, the target drug is administered in a dose-escalating manner or a dose-titration manner.

[1417] In some embodiments, the target drug administration frequency is once a week.

[1418] In some embodiments, the target drug is administered starting with an initial dose, with the dose increased approximately every 4 weeks, with a dose increment of 1 mg to 2 mg (e.g., one or more selected from about 1 mg and about 1.5 mg), and gradually titrated to the maintenance dose of the target drug.

[1419] In some embodiments, the initial dose is about 0.1 mg to about 2.5 mg, for example, the initial dose is about 1.0 mg.

[1420] In some embodiments, the initial dose of the target drug is about 1.0 mg, which is administered for at least 4 weeks; the dose is then increased approximately every 4 weeks, with the dose increment being selected from one or more of about 1 mg and about 1.5 mg, and gradually titrated to a maintenance dose of the target drug of 1.0 mg-5.0 mg (e.g., about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, or about 4.5 mg).

[1421] In some embodiments, the target drug is dose-increased approximately every 4 weeks, and each dose increase is an increase in the dose based on the previous dose, for example, an increase of 1 mg to 2 mg based on the previous dose, for example, an increase of about 1 mg or about 1.5 mg based on the previous dose. In some embodiments, the magnitude of each dose increase is the same or different. For example, the initial dose is about 1 mg, the second dose is about 2 mg, the dose increase is about 1 mg, the third dose is about 3 mg, the dose increase is about 1 mg, and the maintenance dose is 4.5 mg, and the dose increase is about 1.5 mg; for example, the initial dose is about 1 mg, the second dose is about 2 mg, the dose increase is about 1 mg, the third dose is about 3 mg, the dose increase is about 1 mg, and the maintenance dose is 4 mg, and the dose increase is about 1 mg.

[1422] In some embodiments, the maintenance dose is administered once a week.

[1423] In some embodiments, the dosing regimen includes any of the following:

[1424] (1)

[1425] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1426] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1427] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week, e.g., for at least about 2 weeks.

[1428] (2)

[1429] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1430] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1431] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1432] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week, e.g., for at least about 2 weeks;

[1433] (3)

[1434] a) administering about 0.5 mg to about 1.5 mg of the drug of interest once weekly for at least about 1 week, followed by

[1435] b) administering about 2.0 mg to about 3.0 mg of the drug of interest once weekly for at least about 1 week, followed by

[1436] c) administering about 3.0 mg to about 4.5 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1437] d) administering about 1.0 mg to about 6.0 mg of the drug of interest once weekly for at least about 2 weeks, followed by

[1438] e) administering about 1.0 mg to about 6.0 mg of the drug of interest once a week, e.g., for at least about 2 weeks;

[1439] In some embodiments, the dosing regimen comprises any of the following:

[1440] (1) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1441] About 1.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1442] administering about 1.0 mg of the target drug once weekly for at least about 4 weeks;

[1443] (2) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1444] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1445] administering about 2.0 mg of the target drug once weekly for at least about 4 weeks;

[1446] (3) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1447] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1448] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1449] administering about 3.0 mg of the target drug once weekly for at least about 4 weeks;

[1450] (4) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1451] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1452] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1453] administering about 4.5 mg of the target drug once weekly for at least about 4 weeks;

[1454] (5) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1455] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1456] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1457] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1458] administering about 4.0 mg of the target drug once weekly for at least about 4 weeks;

[1459] In some embodiments, the maintenance dose is administered once a week.

[1460] In some embodiments, the dosing regimen comprises any of the following:

[1461] (1) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1462] administering about 0.5 mg to about 10.0 mg of the target drug once a week for at least about 4 weeks, e.g., about 28 weeks;

[1463] (2) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1464] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1465] administering about 0.5 mg to about 10.0 mg of the target drug once a week for at least about 4 weeks, such as about 24 weeks; or,

[1466] (3) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1467] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1468] About 1.0 mg to about 7.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1469] About 0.5 mg to about 10.0 mg of the drug of interest is administered once a week for at least about 4 weeks, such as about 36 weeks.

[1470] In some embodiments, the dosing regimen comprises any of the following:

[1471] (1) administering about 0.5 mg to about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1472] administering about 1.0 mg to about 6.0 mg of the target drug once a week for at least about 4 weeks, e.g., about 28 weeks;

[1473] (2) administering about 0.5 mg to about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1474] About 2.0 mg to about 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1475] administering about 1.0 mg to about 6.0 mg of the target drug once a week for at least about 4 weeks, e.g., about 24 weeks;

[1476] (3) administering 0.5 mg to about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1477] About 2.0 mg to about 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1478] About 3.0 mg to about 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1479] administering about 1.0 mg to about 6.0 mg of the target drug once a week for at least about 4 weeks, such as about 36 weeks; or,

[1480] In some embodiments, the dosing regimen comprises any of the following:

[1481] (1) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1482] administering about 1.0 mg of the target drug once a week for at least about 4 weeks, e.g., about 28 weeks;

[1483] (2) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1484] administering about 2.0 mg of the target drug once a week for at least about 4 weeks, e.g., about 28 weeks;

[1485] (3) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1486] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1487] administering about 3.0 mg of the target drug once a week for at least about 4 weeks, e.g., about 24 weeks;

[1488] (4) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1489] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1490] administering about 4.5 mg of the target drug once a week for at least about 4 weeks, such as about 24 weeks; or,

[1491] (5) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1492] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1493] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1494] About 4.0 mg of the drug of interest is administered once per week for at least about 4 weeks, such as about 36 weeks.

[1495] In some embodiments, the method reduces body weight in the subject.

[1496] In some embodiments, the method improves or reduces at least one of the following indicators in the subject:

[1497] 1) HbA1c;

[1498] 2) the proportion of subjects with HbA1c <7.0%, HbA1c ≤6.5%, or HbA1c <5.7%;

[1499] 3) Fasting plasma glucose, serum insulin, and C-peptide

[1500] 4) plasma glucose, serum insulin, and C-peptide 2 h after a mixed meal;

[1501] 5) pancreatic β-cell function and insulin resistance (HOMA model, such as HOMA-β, HOMA-IR);

[1502] 6) average 7-point self-measured blood glucose (SMBG);

[1503] 7) weight, waist circumference, and BMI;

[1504] 8) the proportion of subjects with a weight loss of ≥5%, ≥10%, or ≥15%;

[1505] 9) proportion of subjects with HbA1c <7.0% and weight loss ≥5%;

[1506] 10) proportion of subjects with HbA1c ≤ 6.5 and weight loss ≥ 10%;

[1507] 11) blood lipids, such as one or more selected from TG, TC, LDL-C, non-HDL-C, and HDL-C;

[1508] 12) Blood pressure, such as systolic and / or diastolic blood pressure.

[1509] In some embodiments, the methods of improving or decreasing are relative to a baseline.

[1510] In some embodiments, the HbA level of the subject after administration according to the disclosed methods is increased compared to baseline. 1c Reduce by at least 2%, at least 2.5%, at least 3%.

[1511] In some embodiments, the subject's body weight is reduced by at least 3%, at least 5%, or at least 10% compared to baseline following administration according to the disclosed dosing methods.

[1512] In some embodiments, the urine protein-to-creatinine ratio of a subject is reduced by at least 15%, at least 30%, at least 45%, or at least 50% compared to baseline following administration according to the disclosed dosing methods.

[1513] In some embodiments, triglycerides in a subject are reduced by at least 10%, at least 20%, at least 25%, or at least 30% compared to baseline following administration according to the disclosed dosing methods.

[1514] In some embodiments, the subject's systolic blood pressure is reduced by at least 5% or at least 10% compared to baseline following administration according to the disclosed dosing methods.

[1515] The present disclosure also provides another exemplary embodiment:

[1516] Embodiment 1. A method for preventing or treating a metabolic disease, comprising administering a target drug to a subject in need thereof approximately once a week, wherein the target drug comprises a GLP-1 analogue having the structure shown below or a pharmaceutically acceptable salt thereof,

[1517] H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGGPSSGAPPPS-NH2.

[1518] Embodiment 2. The method according to embodiment 1, wherein the maintenance dose of the target drug is 0.5 mg-10.0 mg or 1.0 mg-8.0 mg, preferably, the maintenance dose is about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg or about 8.0 mg.

[1519] Embodiment 3. The method according to embodiment 1 or 2, wherein the dose of the target drug is administered in a dose escalation manner.

[1520] Embodiment 4. The method according to any one of embodiments 1-3, wherein the target drug is administered starting from an initial dose, and the dose is increased approximately every 4 weeks, with an increment of 1 mg to 2 mg, and gradually increased to a maintenance dose of the target drug.

[1521] Preferably, the dosage increment is selected from one or more of about 0.5 mg, about 1 mg, about 1.5 mg and about 2.0 mg.

[1522] Preferably, the initial dose is about 0.1 mg to about 2.5 mg, more preferably, the initial dose is about 0.5 mg, about 1.0 mg or about 1.5 mg.

[1523] Embodiment 5. The method of any one of embodiments 1-4, wherein the initial dose of the drug of interest is about 0.5 mg, about 1.0 mg, or about 1.5 mg, administered for at least about 4 weeks;

[1524] The dose is then increased approximately every 4 weeks, with the dose increment being selected from one or more of about 0.5 mg, about 1 mg, about 1.5 mg, and about 2.0 mg, and gradually titrated to a maintenance dose of 1.0 mg to 8.0 mg of the target drug;

[1525] Preferably, the maintenance dose is about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg or about 8.0 mg.

[1526] Embodiment 6. According to any one of embodiments 1-5, the increment of each dose of the target drug is the same or different.

[1527] Embodiment 7. According to the method according to any one of embodiments 1-6, the maintenance dose is administered at a frequency of first once a week and then once every two weeks. Preferably, the maintenance dose of the target drug is first administered once a week for at least about 4 weeks, and then the maintenance dose is administered once every two weeks.

[1528] Embodiment 8. The method according to any one of embodiments 1-7, wherein the dosing regimen comprises any of the following regimens:

[1529] (1) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1530] administering about 0.5 mg to about 10.0 mg of the target drug once weekly for at least about 4 weeks;

[1531] Optionally, about 2.0 mg to about 3.0 mg of the drug of interest is then administered once weekly for at least about 4 weeks, followed by

[1532] administering about 2.0 mg to about 3.0 mg of the target drug once weekly for at least about 4 weeks;

[1533] (2) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1534] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1535] administering about 0.5 mg to about 10.0 mg of the target drug once weekly for at least about 4 weeks; then

[1536] Optionally, thereafter administering about 0.5 mg to about 10.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[1537] (3) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1538] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1539] About 1.0 mg to about 7.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1540] administering about 0.5 mg to about 10.0 mg of the target drug once weekly for at least about 4 weeks;

[1541] Optionally, thereafter administering about 0.5 mg to about 10.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[1542] (4) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1543] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1544] About 1.0 mg to about 7.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1545] About 1.0 mg to about 9 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1546] About 1.0 mg to about 11 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1547] administering about 0.5 mg to about 10.0 mg of the drug of interest once weekly for at least about 4 weeks; or,

[1548] (5) administering about 0.1 mg to about 2.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1549] About 1.0 mg to about 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1550] About 1.0 mg to about 7.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1551] About 1.0 mg to about 9 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1552] About 1.0 mg to about 11 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1553] About 1.0 mg to about 11 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1554] administering about 0.5 mg to about 10.0 mg of the target drug once weekly for at least about 4 weeks;

[1555] (6) administering about 0.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1556] administering about 1.0 mg of the target drug once weekly for at least about 4 weeks;

[1557] Optionally, about 2.0 mg of the drug of interest is then administered once weekly for at least about 4 weeks, followed by

[1558] About 3.0 mg of the drug of interest is administered once weekly for at least about 4 weeks.

[1559] (7) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1560] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1561] administering about 3.0 mg of the target drug once weekly for at least about 4 weeks;

[1562] Optionally, thereafter administering about 3.0 mg of the target drug once every two weeks for at least about 4 weeks;

[1563] (8) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1564] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1565] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1566] administering about 4.5 mg of the target drug once weekly for at least about 4 weeks,

[1567] Optionally, thereafter administering about 4.5 mg of the target drug once every two weeks for at least about 4 weeks;

[1568] (9) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1569] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1570] About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1571] administering about 6.0 mg of the target drug once weekly for at least about 4 weeks,

[1572] Optionally, thereafter administering about 6.0 mg of the drug of interest once every two weeks for at least about 4 weeks;

[1573] (10) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1574] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1575] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1576] administering about 4.0 mg of the target drug once weekly for at least about 4 weeks;

[1577] (11) Administer approximately 1.0 mg of the target drug once a week for approximately 4 weeks, followed by

[1578] administering about 2.0 mg of the target drug once weekly for at least about 4 weeks;

[1579] (12) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1580] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1581] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1582] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1583] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1584] administering about 6.0 mg of the target drug once weekly for at least about 4 weeks; or,

[1585] (13) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by

[1586] About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1587] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1588] About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1589] About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1590] About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1591] administering about 8.0 mg of the target drug once weekly for at least about 4 weeks;

[1592] (14) Administer approximately 1.0 mg of the target drug once a week for approximately 4 weeks, followed by

[1593] administering about 1.0 mg of the target drug once weekly for at least about 4 weeks;

[1594] (15) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by

[1595] About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by

[1596] About 4.5 mg of the drug of interest is administered once weekly for at least about 4 weeks.

[1597] Embodiment 9. The method according to any one of embodiments 1-8, wherein the metabolic disease is obesity or overweight.

[1598] Embodiment 10. A method of improving weight management in a subject in need thereof, comprising administering to the subject a drug of interest according to any one of embodiments 1-8,

[1599] Among them, the target drug is a GLP-1 analogue or a pharmaceutically acceptable salt thereof comprising the structure shown below, H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1600] Embodiment 11. A method of improving glycemic control in a subject in need thereof, comprising administering to the subject a drug of interest according to the method of any one of embodiments 1-8,

[1601] Among them, the target drug is a GLP-1 analogue or a pharmaceutically acceptable salt thereof comprising the structure shown below, H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1602] Embodiment 12. A method for improving blood lipid control in a subject in need thereof, comprising administering to the subject a target drug according to the method of any one of embodiments 1-8,

[1603] Among them, the target drug is a GLP-1 analogue or a pharmaceutically acceptable salt thereof comprising the structure shown below, H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

[1604] Embodiment 13. The method according to any one of embodiments 1-12, wherein the metabolic disease is diabetes, preferably type 2 diabetes.

[1605] Embodiment 14. A method for treating type 2 diabetes in a subject in need thereof, comprising administering a target drug to the subject according to the method of embodiment 13,

[1606] Wherein, the target drug is a GLP-1 analogue or a pharmaceutically acceptable salt thereof comprising the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2,

[1607] Wherein, the subject with type 2 diabetes is at least one of the following:

[1608] 1) Patients whose lifestyle intervention alone is ineffective;

[1609] 2) Metformin or metformin combined with SGLT2 inhibitors is still ineffective

[1610] 3) HbA1c ≥ 7.5% and / or HbA1c ≤ 11%;

[1611] 4) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

[1612] Embodiment 15. The method of embodiment 13 or 14, wherein the subject is also administered metformin, or metformin and an SGLT2 inhibitor.

[1613] Embodiment 16. The method of any one of embodiments 13-15, wherein the method improves or reduces at least one of the following parameters in the subject:

[1614] 1) HbA1c;

[1615] 2) the proportion of subjects with HbA1c <7.0%, HbA1c ≤6.5%, or HbA1c <5.7%;

[1616] 3) Fasting plasma glucose, serum insulin, and C-peptide

[1617] 4) plasma glucose, serum insulin, and C-peptide 2 h after a mixed meal;

[1618] 5) Pancreatic β-cell function and insulin resistance;

[1619] 6) Average 7-point self-test blood sugar;

[1620] 7) weight, waist circumference, and BMI;

[1621] 8) the proportion of subjects with a weight loss of ≥5%, ≥10%, or ≥15%;

[1622] 9) Proportion of subjects with HbA1c < 7.0% and weight loss ≥ 5%

[1623] 10) blood lipids, preferably including one or more of TC, LDL-C, HDL-C and TG;

[1624] 11) Blood pressure, preferably the blood pressure includes systolic pressure and / or diastolic pressure.

[1625] Embodiment 17. The method according to any one of embodiments 1-18, wherein the target drug is a GLP-1 analogue comprising the structure shown below or a pharmaceutically acceptable salt thereof,

[1626] In some embodiments, the target drug is administered parenterally, including but not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some embodiments, the target drug is administered by subcutaneous injection in the abdomen.

[1627] In some embodiments, the target drug is formulated into an injectable form, for example, the pharmaceutical composition comprising the aforementioned target drug further comprises at least one of a buffer, an osmotic pressure regulator, a pH regulator, and an antibacterial agent.

[1628] In some embodiments, the buffer is selected from one or more of acetate buffer, histidine buffer, phosphate buffer, succinate buffer and citrate buffer. In some embodiments, the buffer is a phosphate buffer, such as disodium hydrogen phosphate.

[1629] In some embodiments, the pharmaceutical composition further comprises an osmotic pressure regulator. The osmotic pressure regulator includes, but is not limited to, salts (e.g., sodium chloride, phosphate, sodium citrate, boric acid, and sodium tartrate), sugars or sugar alcohols (lactose, trehalose, sucrose, glucose, mannitol, sorbitol, xylitol), amino acids (e.g., L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine), polyols [e.g., glycerol, 1,2-propylene glycol (also known as propylene glycol in this disclosure), 1,3-propylene glycol, 1,3-butylene glycol], polyethylene glycol (e.g., PEG 400), or a mixture thereof. In some embodiments, the osmotic pressure regulator is selected from one or more of propylene glycol, mannitol, sorbitol, xylitol, glycerol, lactose, trehalose, sucrose, glucose, sodium chloride, phosphate, sodium citrate, boric acid, and sodium tartrate. In some embodiments, the osmotic pressure regulator is sodium chloride. In some embodiments, the osmotic pressure regulating agent is propylene glycol or mannitol.

[1630] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable antibacterial agent. In some embodiments, pharmaceutically acceptable antibacterial agents include, but are not limited to, phenol, o-cresol, m-cresol, p-cresol, methylparaben, propylparaben, 2-phenoxyethanol, butylparaben, 2-phenylethanol, benzyl alcohol, ethanol, chlorobutanol, thimerosal, bronopol, benzoic acid, imidurea, chlorhexidine, sodium dehydroacetate, chlorocresol, ethylparaben, benzethonium chloride, or a mixture thereof. In some embodiments, the pharmaceutically acceptable antibacterial agent is phenol.

[1631] In some embodiments, the pharmaceutical composition is a pharmaceutical composition selected from any components and concentrations disclosed in WO2023083301, and the present disclosure incorporates the compositions, preparation methods, etc. in the aforementioned patents into the present disclosure by reference.

[1632] In some embodiments, administration of the target drug using the dosage regimen provided by the present disclosure can significantly reduce the weight of obese subjects and has benefits on both sugar and lipid metabolism.

[1633] In some embodiments, compared to other GLP-1 analogs (e.g., dual agonists of the GLP-1 receptor and the GIP receptor, such as tilportide), administration of the aforementioned target drugs using the dosing regimen provided by the present disclosure results in superior weight control and / or blood sugar control.

[1634] In some embodiments, compared with other GLP-1 analogs (such as dual agonists of GLP-1 receptor and GIP receptor, such as tilportide), the administration of the aforementioned target drug using the dosing regimen provided by the present disclosure has a superior dosage advantage.

[1635] In some embodiments, compared to other GLP-1 analogs (e.g., dual agonists of the GLP-1 receptor and the GIP receptor, such as tilportide), administration of the aforementioned target drugs using the dosing regimen provided by the present disclosure has reduced adverse reactions, such as a reduced risk of hypoglycemia, such as a reduced risk of severe hypoglycemia.

[1636] In some embodiments, the present disclosure provides a method for reducing the risk of hypoglycemia (e.g., severe hypoglycemia) in a subject, comprising administering the aforementioned target drug using a dosing regimen provided by the present disclosure, for example, the subject suffers from a metabolic disease, such as type 2 diabetes.

[1637] the term

[1638] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[1639] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to."

[1640] "About" and "approximately" refer to values ​​within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each instance of a number or numerical range preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[1641] The term "and / or," such as "X and / or Y," should be understood to mean "X and Y" or "X or Y" and should be used to provide clear support for both meanings or either meaning.

[1642] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[1643] The term "native GLP-1" refers to naturally occurring molecules of the glucagon family or the exendin family of peptides, wherein: the glucagon family of peptides is encoded by the preproglucagon gene and includes three small peptides with high homology, namely glucagon (1-29), GLP-1 (1-37) and GLP-2 (1-33); exendins are peptides expressed in lizards and, similar to GLP-1, are insulinotropic. In some embodiments, the term "native GLP-1" also refers to human GLP-1 (7-37) and human GLP-1 (7-36). The term "native GIP" refers to a peptide comprising the sequence of human GIP (1-42).

[1644] The term "GLP-1 analogue" refers to an analogue having up to 25, up to 24, up to 23, up to 22, up to 21, up to 20, up to 19, up to 18, up to 17, up to 16, up to 15, up to 14, up to 13, up to 12, up to 11, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2, or 1 amino acid modification or chemical modification compared to native GLP-1 (in particular compared to human GLP-1 (7-37) and human GLP-1 (7-36)), wherein the amino acid modification may be an amino acid substitution, addition and / or deletion; the chemical modification may be a chemical modification selected from the following groups: amide, carbohydrate, alkyl, acyl, ester, polyethylene glycol (PEG) group, sialylation group, glycosylation group, etc.

[1645] In some embodiments, the GLP-1 analog is a GLP-1 receptor agonist. In some embodiments, the GLP-1 analog is a dual agonist of the GLP-1 receptor and the GIP receptor.

[1646] The term agonist is defined as a substance that activates the receptor type in question, and "activity," "activation," "activation," and the like refer to assays as determined using assays known in the art.

[1647] An amino acid "substitution" as described herein refers to the replacement of one amino acid residue with a different one.

[1648] The term "peptide" as used in this disclosure encompasses peptides with modified amino and carboxyl termini. For example, an amino acid chain containing an amide group in place of the terminal carboxylic acid is also included in the amino acid sequence designated as a natural amino acid.

[1649] The hydrogen atoms described in the present disclosure can all be replaced by their isotopes (protium, deuterium, tritium), and any hydrogen atom in the compounds of the present disclosure involved in the present disclosure can also be replaced by isotope atoms.

[1650] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[1651] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by substituents. Substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g., olefinic) bonds.

[1652] A "pharmaceutical composition" is a composition comprising one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or

[1653] A mixture of a prodrug and other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert its biological activity.

[1654] "Buffer" refers to a buffer that tolerates changes in pH through the action of its acid-base conjugate components. Examples of buffers that control pH within an appropriate range include acetate, succinate, citrate, phosphate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine, and other organic acid buffers.

[1655] The three letter and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[1656] "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ or a biological fluid, refers to the contacting of an exogenous drug, therapeutic agent, diagnostic agent or composition with an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid. "Administering" and "treating" can refer to, for example, therapeutic, pharmacokinetics, diagnostics, research and experimental procedures. Treatment of cells includes contacting an agent with a cell, and contacting an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean treating, for example, a cell in vitro and ex vivo, by an agent, a diagnostic, a binding composition or by another cell. "Treatment" as applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[1657] "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[1658] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[1659] As used herein, "glycemic control" refers to managing glucose metabolism indicators, for example, maintaining or reducing fasting plasma glucose, fasting serum insulin, glycosylated hemoglobin (HbA1c), insulin resistance (HOMA model), etc.

[1660] As used herein, "weight control" or "weight management" refers to managing obesity or overweight in an individual; "improving" weight management refers to weight loss.

[1661] As used herein, a "titrated dose" or "escalating dose" refers to a dose that is less than the maximum effective dose required for a patient. As used herein, the present invention contemplates that a "titrated dose" or "escalating dose" can be changed to the maximum effective dose required, or can be changed to a "maintenance dose" if it is observed that this dose is the effective dose required for the patient.

[1662] As used herein, "maintenance dose" refers to a dose that is the highest effective dose required for a patient, and when the maintenance dose is less than the highest effective dose required, this maintenance dose can become an ascending dose. That is, if the maintenance dose of "about 4.5 mg" encompassed by the present invention is not the highest effective dose required for a particular patient, then the 4.5 mg maintenance dose will in turn become an ascending dose, as the dose for that particular patient will be increased until the next highest maintenance dose encompassed by the present disclosure, e.g., 6.0 mg, is achieved for at least about 2 weeks.

[1663] As used herein, "pharmaceutically acceptable salts" are well known to those skilled in the art. In one embodiment, the GLP-1 analog is in the form of a pharmaceutically acceptable salt. In one embodiment, the GLP-1 analog is in the form of a non-salt.

[1664] The terms "subject" and "patient" refer to mammals, particularly primates, and especially humans. DETAILED DESCRIPTION

[1665] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples herein where specific conditions are not specified generally follow conventional conditions, such as those in the Cold Spring Harbor Laboratory's "Antibody Techniques Laboratory Manual" and "Molecular Cloning Manual," or according to the conditions recommended by the raw material or product manufacturer. Reagents where the specific source is not specified are commercially available.

[1666] Example 1. Preparation of GLP-1 analogs

[1667] The GLP-1 analog is compound 18# prepared in Example 1 of WO2023083301 (incorporated herein by reference in its entirety),

[1668] The molecular structure of compound 18# is: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2

[1669] The structural formula is as follows:

[1670] Example 2. Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GLP-1 Analog Injection

[1671] A randomized, double-blind, dose-escalation, placebo-controlled Phase I clinical study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple subcutaneous injections of a GLP-1 analogue.

[1672] After a single subcutaneous injection of GLP-1 analogues in healthy subjects, the drug was slowly absorbed within the dose range of 0.1 to 8.1 mg, with the median time to peak concentration in each dose group ranging from 48 to 72 hours. After peak concentration, drug concentration was eliminated in a monoexponential manner, with the terminal elimination half-life (t 1 / 2 ) arithmetic mean of 156 to 182 hours; mean residence time (MRT) geometric mean of 251 to 288 hours. After the fourth subcutaneous injection of 0.9, 2.7, and 5.4 mg of GLP-1 analogue injection in healthy subjects on day 22, the drug was slowly absorbed, with the median time to peak in each dose group ranging from 48 to 72 hours. After peak, drug concentrations were eliminated in a monoexponential manner, with t 1 / 2 The arithmetic mean is 169 to 192 hours; the geometric mean of MRT is 279 to 303 hours. ss / F) geometric mean 27.7 ~ 41.1ml / h, steady-state apparent distribution volume (V ss The geometric mean of the dose ranged from 7.61 to 10.2 L. The cumulative exposure ratio of 0.9 and 2.7 mg D22 was approximately 2-fold.

[1673] Healthy subjects were given subcutaneous injections of GLP-1 analogues weekly for 4 consecutive weeks (D29, QW). The changes in body weight relative to baseline in the placebo group, 0.9 mg, 2.7 mg, and 5.4 mg (2.7 / 2.7 / 4.0 / 5.4 mg, titration) GLP-1 analogue injection groups were: -1.15 kg (-1.35%), -4.29 kg (-6.72%), -5.94 kg (-7.38%), and -7.73 kg (-9.63%), respectively. The weight loss effect of each dose group of GLP-1 analogue was significantly better than that of the placebo group.

[1674] In the Phase I study, 72 subjects received single or multiple doses of GLP-1 analogs in doses ranging from 0.1 to 8.1 mg. Among these 72 subjects, the incidence of GLP-1 analog-related adverse events (AEs) was 65.3% (47 / 72). The most common AEs were abdominal distension and nausea in the single-dose escalation phase and urinary ketones and nausea in the multiple-dose escalation phase. All AEs were mild or moderate (mostly mild), with no severe hypoglycemia or serious adverse events.

[1675] Example 3. A multicenter, randomized, double-blind, placebo-controlled phase II clinical study to evaluate the efficacy and safety of GLP-1 analog injection in obese non-diabetic subjects

[1676] 1. Trial Drug

[1677] 1) The GLP-1 analogue prepared in Example 1 is in the form of an injection with a specification of 3 ml: 30 mg.

[1678] 2. Enrollment of subjects

[1679] Subjects must meet all of the following criteria to enter this study:

[1680] 1) Age range: 18 to 65 years old (inclusive), regardless of gender;

[1681] 2). Body mass index (BMI) at screening: 28.0-40.0 kg / m 2 (including both ends);

[1682] 3) Self-reported diet and exercise control for 3 months or more before screening, and weight change in the past 3 months (the difference between the maximum and minimum weights in the past 3 months) did not exceed 5 kg.

[1683] 3. Dosage regimen

[1684] GLP-1 analog injection or placebo is administered subcutaneously in the abdomen, either before or after meals. The specific dosing schedule is as follows:

[1685] Table 1. Dosage regimens for the first treatment period (weeks 0 to 23) and the second treatment period (weeks 24 to 31)

[1686] Table 2. Dosage regimen for the second treatment period (weeks 32 to 51)

[1687] 4. Results Evaluation

[1688] 4.1 Effectiveness Evaluation

[1689] Effectiveness evaluation indicators include weight, waist circumference, BMI, blood pressure (systolic pressure, diastolic pressure), glucose metabolism (fasting plasma glucose, fasting serum insulin, insulin resistance (HOMA model*), HbA1c), and blood lipids (TC, LDLC, HDL-C, TG).

[1690] *Note: Homeostasis model assessment (HOMA) insulin resistance (HOMA-IR) was calculated using the following formula:

[1691] HOMA-IR = [fasting blood glucose level (FPG, mmol / L) × fasting insulin level (FINS, mIU / L)] / 22.5

[1692] 4.2 Safety evaluation

[1693] Safety evaluation indicators include adverse events, laboratory indicators, 12-lead electrocardiogram, vital signs, physical examination, PHQ-9 score, etc.

[1694] 4.3 Results

[1695] 249 people with a body mass index of 28-40 kg / m 2 Chinese adults received subcutaneous injection of GLP-1 analogues (1.0 mg QW group, 3.0 mg QW group, 4.5 mg QW group, 6.0 mg QW group) or placebo once a week for 24 weeks (24W) according to the dosing regimen of the first treatment period shown in Table 1.

[1696] At Week 24, the mean percentage change from baseline in body weight was -5.4% (95% CI -7.3% to -3.5%) in the 1.0 mg QW group, -13.4% (-15.2% to -11.5%), -14.0% (-15.9% to -12.1%), and -16.8% (-18.8% to -14.9%) in the 3.0 mg QW group, 4.5 mg QW group, and 6.0 mg QW group, respectively, compared with -0.1% (-2.1% to 1.8%) in the placebo group (P < 0.0001 for all comparisons with placebo). The proportion of participants who achieved a ≥5% weight loss was 52.0%, 88.2%, 92.0%, 91.8%, and 10.2% in the 1.0 mg QW group, 3.0 mg QW group, 4.5 mg QW group, and 6.0 mg QW group, respectively. In addition, GLP-1 analogs were more effective than placebo in lowering blood pressure, regulating blood glucose levels, inhibiting insulin resistance, and reducing triglyceride levels. At W24, the least squares mean change in systolic blood pressure compared to baseline in the GLP-1 analog group ranged from -4.46 to -8.33 mmHg (placebo: -0.41 mmHg), and the least squares mean change in waist circumference compared to baseline in the GLP-1 analog group ranged from -5.14 to -12.73 cm (placebo: -1.82 cm). Most adverse events (AEs) were mild or moderate in severity, with the most common adverse events being nausea, diarrhea, decreased appetite, and vomiting, which primarily occurred during the dose escalation period. No serious adverse reactions related to treatment occurred, and no participant discontinued treatment due to treatment-related adverse reactions.

[1697] Conclusions: GLP-1 analogs can effectively reduce body weight, blood pressure, blood glucose, and triglycerides with a favorable safety profile. These data support further clinical development of GLP-1 analogs for the treatment of obesity.

[1698] Example 4. A multicenter, randomized, double-blind, placebo-controlled phase II clinical study to evaluate the efficacy and safety of GLP-1 analog injection in subjects with type 2 diabetes

[1699] 1. Trial Drug

[1700] 1) The GLP-1 analogue prepared in Example 1 is in the form of an injection.

[1701] 2. Enrollment of subjects

[1702] Subjects must meet all of the following criteria to enter this study:

[1703] 1) Age range: 18 to 65 years old (including the critical value), regardless of gender;

[1704] 2) diagnosed with type 2 diabetes according to the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2020 Edition)" and meeting the diagnostic criteria for at least 6 months;

[1705] 3) Patients had undergone simple lifestyle intervention for at least 8 weeks before screening, or had been treated stably with metformin alone (daily dose ≥ 1000 mg) for at least 8 weeks. Stable treatment was defined as no change in medication or daily dose.

[1706] 4) 7.5% ≤ HbA1c ≤ 10.5% at screening;

[1707] 5) Body mass index (BMI) 22.0-40.0 kg / m at screening 2 (including both ends);

[1708] 6) The weight change within 3 months before screening (the difference between the maximum weight and the minimum weight within 3 months) does not exceed 5kg.

[1709] 3. Dosage regimen

[1710] The test drug was administered by subcutaneous injection in the abdomen once a week, either before or after meals.

[1711] In the first treatment period (weeks 0-19), the dosage of GLP-1 analog injection was 1.0 mg, 2.0 mg, 3.0 mg, 4.5 mg, and placebo, and the treatment lasted for 20 weeks.

[1712] The dosage of the second treatment period (20-31 weeks) maintained the GLP-1 analog injection / placebo dosage of the first treatment period. The original trial drug group was given an additional placebo, and the original placebo group was given an additional 1.0 mg of trial drug for 12 weeks.

[1713] The specific dosage regimen is as follows:

[1714] Table 3. Dosing regimens for the first treatment period (weeks 0-19) and the second treatment period (weeks 20-31) *Note: The second treatment period is 2 injections per week (including 1 injection of GLP-1 analogue and 1 injection of placebo)

[1715] 4. Results Evaluation

[1716] 4.1 Effectiveness Evaluation

[1717] Effectiveness evaluation indicators include HbA1c, plasma glucose 2 hours after fasting and mixed meal, serum insulin and C-peptide 2 hours after fasting and mixed meal, pancreatic β-cell function and insulin resistance (HOMA model), 7-point SMBG spectrum, body weight, waist circumference, blood lipids (TC, LDL-C, HDL-C, TG), blood pressure (systolic pressure, diastolic pressure), etc.

[1718] 4.2 Safety evaluation

[1719] Adverse events, hypoglycemic events, laboratory indicators, 12-lead electrocardiogram, vital signs, etc.

[1720] 4.3 Results

[1721] 199 subjects with type 2 diabetes were randomly assigned in a 1:1:1:1:1 ratio to receive a subcutaneous injection of a GLP-1 analogue (1.0 mg, 2.0 mg, 3.0 mg, and 4.5 mg) or placebo once weekly for 20 weeks. The primary endpoint was HbA1c after 20 weeks of treatment. 1c ) Changes from baseline.

[1722] HbA in the five study groups 1c Baseline levels were comparable, with average levels ranging from 8.2% to 8.7%. As of the data cutoff date (May 1, 2024), 187 of the 199 subjects (94.0%) completed the 20-week study treatment. At week 20, HbA levels in the GLP-1 analogue 1.0 mg, 2.0 mg, 3.0 mg, and 4.5 mg groups were significantly higher than those in the control group (P < 0.05). 1c The least squares mean (LS Mean) changes from baseline were -2.1% (95% CI -2.4% to -1.9%), -2.6% (95% CI -2.8% to -2.3%), -2.7% (95% CI -2.9% to -2.4%), and -2.5% (95% CI -2.7% to -2.2%) for the sedative group, respectively, compared to -0.3% (95% CI -0.6% to 0%) for the placebo group (one-sided p < 0.0001 for all comparisons relative to the placebo group). At week 20, the proportions of subjects achieving the target HbA1c <7.0% in the GLP-1 analog 1.0 mg, 2.0 mg, 3.0 mg, and 4.5 mg groups were 75.0%, 90.2%, 84.6%, and 90.0% (placebo group: 12.8%), the proportions of subjects achieving HbA1c ≤6.5% were 62.5%, 80.5%, 69.2%, and 90.0% (placebo group: 2.6%), and the proportions of subjects achieving HbA1c <5.7% were 17.5%, 26.8%, 28.2%, and 35.0% (placebo group: 0%).

[1723] Compared with baseline, the LS Mean changes in body weight at week 20 were -3.1%, -4.9%, -5.5% and -7.1% for the GLP-1 analog 1.0 mg group, 2.0 mg group, 3.0 mg group and 4.5 mg group, respectively (placebo: -0.6%).

[1724] Compared with baseline, the LS Mean changes in urine protein-creatinine ratio (UACR) at week 20 were -18.1%, -30.5%, -46.5% and -49.5% in the 1.0 mg, 2.0 mg, 3.0 mg and 4.5 mg GLP-1 analogue groups, respectively (placebo: 2.5%).

[1725] Compared with baseline, the LS Mean changes in triglyceride (TG) at week 20 were -10.0%, -25.9%, -25.7% and -27.9% for the GLP-1 analog 1.0 mg group, 2.0 mg group, 3.0 mg group and 4.5 mg group, respectively (placebo: -6.9%).

[1726] Compared with baseline, the LS Mean changes in systolic blood pressure (SBP) at week 20 were -8.3%, -7.4%, -10.0% and -6.7% for the GLP-1 analog 1.0 mg group, 2.0 mg group, 3.0 mg group and 4.5 mg group, respectively (placebo: -1.2%).

[1727] In addition, at week 20, all doses of GLP-1 analogues were superior to placebo in reducing fasting plasma glucose, 2-hour postprandial plasma glucose, 7-point self-measured blood glucose, and systolic blood pressure.

[1728] Most adverse events in the GLP-1 analogue group were mild or moderate, with the most common being diarrhea, decreased appetite, nausea, abdominal distension, and upper respiratory tract infection, as shown in Table 4. The incidence of serious adverse events was comparable between the GLP-1 analogue and placebo groups. No clinically significant (<3 mmol / L) or severe hypoglycemia was reported.

[1729] Table 4: Adverse Reactions

[1730] In the metformin subgroup, HbA1c in the GLP-1 analogue 1.0 mg, 2.0 mg, 3.0 mg, and 4.5 mg groups at week 20 was significantly higher than that in the metformin group. 1c The LS Mean changes from baseline were -2.0% (95% CI -2.4% to -1.6%), -2.4% (95% CI -2.8% to -2.0%), -2.9% (95% CI -3.3% to -2.5%), and -2.2% (95% CI -2.6% to -1.8%), respectively, compared to -0.1% (95% CI -0.4% to 0.5%) in the placebo group (one-sided p < 0.0001 for all comparisons relative to placebo). In the metformin-naive subgroup, HbA1c levels in the GLP-1 analogue 1.0 mg, 2.0 mg, 3.0 mg, and 4.5 mg groups at Week 20 were significantly higher than those in the placebo group (P < 0.0001). 1cThe LS Mean changes from baseline were -2.3% (95% CI -2.7% to -2.0%), -2.7% (95% CI -3.1% to -2.4%), -2.5% (95% CI -2.9% to -2.2%), and -2.7% (95% CI -3.1% to -2.4%), respectively, compared to -0.7% (95% CI -1.0% to 0.3%) in the placebo group (one-sided p < 0.0001 for all comparisons relative to the placebo group).

[1731] Conclusions: Compared with placebo, GLP-1 analogs demonstrated superior glycemic control and weight loss in patients with T2DM, with an acceptable safety profile and a low risk of hypoglycemia. These data support further clinical development of GLP-1 analogs for the treatment of T2DM.

[1732] Example 5. Study on the Effect of GLP-1 Analog Injection on Metformin Pharmacokinetics in Healthy Subjects

[1733] 1. Trial Drug

[1734] 1) The GLP-1 analogue prepared in Example 1 is in the form of an injection.

[1735] 2) Commercially available metformin hydrochloride tablets (Gezhihua), Merck Pharmaceuticals Co., Ltd.

[1736] 2. Enrollment of subjects

[1737] Key inclusion criteria:

[1738] 1. Healthy men aged 18 to 45 years (including the critical value);

[1739] 2. Male weight ≥ 50 kg, body mass index (BMI) between 20.0 and 30.0 kg / m 2 (including critical value);

[1740] 3. Glycated hemoglobin (HbA1c) <6.0%.

[1741] 3. Experimental Purpose

[1742] Main research objectives:

[1743] To evaluate the effect of a single 2 mg subcutaneous injection of a GLP-1 analog injection on metformin exposure in healthy subjects.

[1744] Secondary study objectives:

[1745] To evaluate the effects of a single 2 mg subcutaneous injection of a GLP-1 analog injection on other pharmacokinetic (PK) parameters of metformin in healthy subjects.

[1746] To evaluate the safety of a single subcutaneous injection of 2 mg of GLP-1 analogue injection combined with metformin hydrochloride tablets in healthy subjects.

[1747] To evaluate the PK characteristics of a single 2 mg subcutaneous injection of a GLP-1 analog in healthy subjects.

[1748] 4. Dosage regimen

[1749] Metformin hydrochloride tablets (Glucophage): Starting on day 1, take 500 mg orally twice daily (BID) after standard meals in the morning and evening. Continue orally for 3.5 days until breakfast on day 4. Start the second round of oral administration after breakfast on day 7, also at 500 mg, BID, for 3.5 days until breakfast on day 10. Maintain consistent dosing times daily.

[1750] A single subcutaneous injection of 2 mg of GLP-1 analogue solution was administered on the morning of day 7 (before oral administration of metformin hydrochloride tablets).

[1751] 5.PK evaluation

[1752] A validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method was used to measure the concentrations of metformin and GLP-1 analogs in plasma, and a standard non-compartmental model was used to calculate PK parameters.

[1753] 6. Security

[1754] Adverse events, physical examination, vital signs, laboratory tests and 12-lead electrocardiogram, etc.

[1755] Example 6. Comparison of the efficacy and safety of GLP-1 analogs and semaglutide in subjects with type 2 diabetes who have poor glycemic control on metformin alone or in combination with a sodium-glucose cotransporter 2 (SGLT2) inhibitor

[1756] 1. Trial Drug

[1757] 1) The GLP-1 analogue prepared in Example 1 is in the form of an injection.

[1758] 2) Commercially available semaglutide injection, Novo Nordisk, Denmark.

[1759] 2. Trial Population

[1760] Metformin alone or in combination with an SGLT2 inhibitor is used to treat patients with type 2 diabetes who have poor glycemic control.

[1761] 3. Enrollment of subjects

[1762] Key inclusion criteria:

[1763] 1. Age ≥ 18 years old, regardless of gender;

[1764] 2. Diagnosed with type 2 diabetes according to the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2020 Edition)", and meeting the diagnostic criteria for more than 90 days at the time of screening;

[1765] 3. Stable treatment with antidiabetic drugs from 3 months before screening to before randomization: metformin alone, or metformin combined with an SGLT2 inhibitor;

[1766] Note: Stable treatment is defined as no change in the drug and total daily dose, metformin dose ≥1500 mg / day or maximum tolerated dose (≥1000 mg / day); SGLT2 inhibitor dose is the daily dose recommended in the instructions.

[1767] 4. 7.5% ≤ HbAlc ≤ 11.0% at screening;

[1768] 5. Body mass index (BMI) ≥ 24.0 kg / m at screening 2 ;

[1769] 6. The weight change (the difference between the maximum and minimum weight within 3 months) within 3 months before screening (including the screening visit) does not exceed 5kg.

[1770] 4. Dosage regimen

[1771] GLP-1 analogs or semaglutide are administered subcutaneously once weekly (QW) in the abdomen, thigh, or outer upper arm, either before or after meals.

[1772] The target doses in the first treatment period were 2 mg of GLP-1 analog (titrated for 4 weeks), 4 mg of GLP-1 analog (titrated for 12 weeks) and 1 mg of semaglutide (titrated for 8 weeks), with a treatment period of 36 weeks.

[1773] During the second treatment period, the dosage of GLP-1 analog injection / semaglutide used in the first treatment period remained unchanged, and the treatment period lasted 16 weeks. The specific dosing regimen for each group was as follows:

[1774] Table 5: Dosage regimen Note: QW = once a week

[1775] 5. Results Evaluation

[1776] 5.1 Effectiveness Evaluation

[1777] Effectiveness evaluation indicators include HbA1c, fasting and mixed meal 2-hour plasma glucose, fasting and mixed meal 2-hour serum insulin and C-peptide, insulin β-cell function (HOMA-β), insulin resistance (HOMA-IR), average 7-point self-measured blood glucose (SMBG), weight, waist circumference, BMI, blood pressure (systolic pressure, diastolic pressure), blood lipids (TG, TC, LDL-C, non-HDL-C, HDL-C), etc.

[1778] 5.2 Safety evaluation

[1779] Safety evaluation indicators include AE, hypoglycemic events, laboratory indicators, electrocardiogram, vital signs, physical examination, etc.

[1780] Example 7. A multicenter, randomized, double-blind, placebo-controlled phase III clinical study to evaluate the efficacy and safety of GLP-1 analog injection in overweight or obese subjects

[1781] 1. Trial Drug

[1782] 1) The GLP-1 analogue prepared in Example 1 is in the form of an injection with the following specifications: 3 ml: 12 mg, 3 ml: 24 mg, and 3 ml: 30 mg.

[1783] 2. Enrollment of subjects

[1784] Subjects must meet all of the following criteria to enter this study:

[1785] 1) Age ≥ 18 years old, regardless of gender;

[1786] 2) BMI meets the following criteria during screening:

[1787] ≥28.0kg / m 2 ,or

[1788] ≥24.0kg / m 2 and have at least one weight-related comorbidity:

[1789] 3) Self-reported diet and exercise control for 3 months or more before screening, and weight change in the past 3 months (the difference between the maximum and minimum weights in the past 3 months) ≤ 5kg.

[1790] 3. Dosage regimen

[1791] GLP-1 analog injection or placebo is administered subcutaneously in the abdomen, outer thigh, or outer upper arm, either before or after a meal. The specific dosing regimen is as shown in Table 6 below:

[1792] Table 6. Dosage regimen

[1793] 4. Results Evaluation

[1794] 4.1 Effectiveness Evaluation

[1795] Effectiveness evaluation indicators include weight, waist circumference, BMI, blood pressure (systolic pressure, diastolic pressure), blood lipids (TG, TC, LDL-C, non-HDL-C, HDL-C), glucose metabolism (fasting plasma glucose, fasting serum insulin, HbA1c, HOMA-IR), physiological function score (SF-36v2), hsCRP, total fat mass, lean body mass, and UACR.

[1796] *Note: Homeostasis model assessment (HOMA) insulin resistance (HOMA-IR) was calculated using the following formula: HOMA-IR = [fasting blood glucose level (FPG, mmol / L) × fasting insulin level (FINS, mIU / L)] / 22.5

[1797] 4.2 Safety evaluation

[1798] Safety evaluation indicators include adverse events, vital signs, physical examination, laboratory indicators, 12-lead electrocardiogram, PHQ-9 score, etc.

[1799] Example 8. A multicenter, randomized, double-blind, placebo-controlled clinical study to evaluate the efficacy and safety of GLP-1 analog injection in overweight or obese subjects

[1800] 1. Trial Drug

[1801] 1) The GLP-1 analogue prepared in Example 1 is in the form of an injection.

[1802] 2. Trial Population

[1803] Overweight subjects with at least one weight-related comorbidity or obese subjects who are not well controlled by diet and exercise alone.

[1804] 3. Enrollment of subjects

[1805] Subjects must meet all of the following criteria to enter this study:

[1806] 1) Applicants must be between 18 and 65 years old (inclusive), regardless of gender;

[1807] 2) Body mass index (BMI) meets the following criteria during screening:

[1808] -28.0-40.0kg / m 2 (inclusive), or

[1809] -24.0 (inclusive) -28.0 (exclusive) kg / m 2and at least one weight-related comorbidity

[1810] 3) Self-reported diet and exercise control for 3 months or more before screening, and weight change (the difference between the maximum and minimum weights in the past 3 months) within the past 3 months did not exceed 5 kg;

[1811] 3. Dosage regimen

[1812] GLP-1 analog injection or placebo was administered subcutaneously once weekly, either before or after meals. The dose of GLP-1 analog injection or placebo was initiated at 1.0 mg QW and titrated every 4 weeks to a target dose of 8.0 mg QW. The specific dosing regimen was as shown in Table 7 below:

[1813] Table 7: Dosage regimen

[1814] 4. Results Evaluation

[1815] 4.1 Effectiveness Evaluation

[1816] Effectiveness evaluation indicators include weight, waist circumference, BMI, blood pressure (systolic pressure, diastolic pressure), glucose metabolism (fasting plasma glucose, fasting serum insulin, HbA1c), and blood lipids (TG, TC, LDL-C, non-HDL-C, HDL-C).

[1817] 4.2 Safety evaluation

[1818] Safety evaluation indicators include adverse events, laboratory indicators, 12-lead electrocardiogram, vital signs, physical examination, PHQ-9 score, etc.

[1819] 4.3 Results

[1820] After 36 weeks of administration, the percentage change in body weight of subjects in the GLP-1 analog 8.0 mg group compared with baseline was -22.82%, and the least squares mean of the difference compared with the placebo group was -21.09%, which was significantly better than the placebo.

[1821] After 36 weeks of dosing, the proportion of subjects in the GLP-1 analog 8.0 mg group who had lost ≥20% of their body weight was 59%.

[1822] The 8.0 mg GLP-1 analogue group had a favorable safety profile. Most adverse events were mild. Gastrointestinal adverse events primarily occurred during the dose escalation phase.

Claims

1. A method for preventing or treating a metabolic disease, comprising administering a target drug to a subject in need thereof approximately once a week, wherein: The dosing regimen of the target drug includes: An initial dose of the drug of interest is administered once a week for at least about 1 week, and then, Optionally, increasing doses of the drug of interest are administered once a week for at least about 1 week, followed by administering a maintenance dose of the target drug once a week for at least about 2 weeks; Wherein, the maintenance dose is selected from about 0.5 mg to about 10.0 mg, or about 1.0 mg to about 8.0 mg; preferably about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg or about 8.0 mg; Wherein, the target drug is selected from GLP-1 analogs or pharmaceutically acceptable salts thereof.

2. The method according to claim 1, wherein: The target drug is a dual agonist of GLP-1 receptor and GIP receptor, preferably a GLP-1 analogue or a pharmaceutically acceptable salt thereof having the structure shown below: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

3. The method according to claim 1 or 2, wherein: The initial dose is selected from about 0.1 mg to about 2.5 mg, or about 0.5 mg to about 1.5 mg; preferably about 0.5 mg, about 1.0 mg or about 1.5 mg.

4. The method according to any one of claims 1 to 3, wherein: The increasing dose is selected from about 0.5 mg to about 10.0 mg, about 1.0 mg to about 6.0 mg; preferably about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg or about 6.0 mg.

5. The method according to any one of claims 1 to 4, wherein: The increasing dose includes at least one of a second dose, a third dose, a fourth dose, a fifth dose, and a sixth dose; The second dose is selected from about 1.0 mg to about 5.0 mg, or about 2.0 mg to about 3.0 mg; preferably about 2.0 mg or about 3.0 mg; The third dose is selected from about 1.0 mg to about 7.5 mg, or about 3.0 mg to about 4.5 mg; preferably about 3.0 mg or about 4.5 mg; The fourth dose is selected from about 1.0 mg to about 9.0 mg, or about 4.0 mg to about 5.0 mg; preferably about 4.0 mg; The fifth dose is selected from about 1.0 mg to about 11.0 mg, or about 5.0 mg to about 6.0 mg; preferably about 5.0 mg; The sixth dose is selected from about 1.0 mg to about 11.0 mg, or about 6.0 mg to about 7.0 mg; preferably about 6.0 mg.

6. The method according to any one of claims 1 to 5, wherein: administering the initial dose of the target drug for at least about 2 weeks, preferably about 4 weeks; and / or, administering increasing doses of the drug of interest for at least about 2 weeks, preferably about 4 weeks; and / or, Administer a maintenance dose of the target drug for at least about 4 weeks.

7. The method according to any one of claims 1 to 6, wherein: The administration regimen of the target drug includes the following regimen: a) administering about 1.0 mg of the target drug once a week for at least about 2 weeks; then d) administering about 1.0 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 0.5 mg of the target drug once a week for at least about 2 weeks, followed by d) administering about 1.0 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by d) administering about 2.0 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 2 weeks, followed by d) administering about 3.0 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 2 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 2 weeks, followed by d) administering about 4.5 mg of the target drug once a week for at least about 4 weeks; or a) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 2 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 2 weeks, followed by d) administering about 4.0 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 1.5 mg of the target drug once a week for at least about 2 weeks, followed by b) administering about 3.0 mg of the target drug once a week for at least about 2 weeks, followed by d) administering about 4.5 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 1.5 mg of the target drug once a week for at least about 2 weeks, followed by b) administering about 3.0 mg of the target drug once a week for at least about 2 weeks, followed by c) administering about 4.5 mg of the target drug once a week for at least about 2 weeks, followed by d) administering about 6.0 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 2 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 2 weeks, followed by About 4.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 5.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by d) administering about 6.0 mg of the target drug once a week for at least about 4 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 2 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 2 weeks, followed by About 4.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 5.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 6.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by d) administering about 8.0 mg of the drug of interest once per week for at least about 4 weeks.

8. The method according to any one of claims 1 to 7, wherein: The dosing regimen of the target drug includes the following regimen: a) administering about 1.0 mg of the target drug once a week for at least about 4 weeks; then d) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, such as about 20 weeks; or, a) administering about 0.5 mg of the target drug once a week for at least about 4 weeks, followed by d) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, such as about 20 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by d) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, such as about 20 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, followed by d) administering about 3.0 mg of the target drug once a week for at least about 4 weeks, such as about 16 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 4 weeks, followed by d) administering about 4.5 mg of the target drug once a week for at least about 4 weeks, such as about 12 weeks; or, a) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by b) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, followed by d) administering about 4.5 mg of the target drug once a week for at least about 4 weeks, such as about 16 weeks; or, a) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by b) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, followed by c) administering about 4.5 mg of the target drug once a week for at least about 4 weeks, followed by d) administering about 6.0 mg of the target drug once a week for at least about 4 weeks, such as about 12 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 4 weeks, followed by d) administering about 4.0 mg of the target drug once a week for at least about 4 weeks, such as about 12 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 4 weeks, followed by About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by d) administering about 6.0 mg of the target drug once a week for at least about 4 weeks, such as about 4 weeks; or, a) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by b) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, followed by c) administering about 3.0 mg of the target drug once a week for at least about 4 weeks, followed by About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by d) administering about 8.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 12 weeks.

9. The method according to any one of claims 1 to 8, wherein: The dosing regimen also includes two treatment periods, and the second treatment period includes: 1) administering a maintenance dose of the target drug once a week for at least about 1 week; or, 2) administering a maintenance dose of the target drug every two weeks for at least about 2 weeks; or, 3) Administer maintenance doses of the target drug once a week for at least about 1 week, followed by Administer maintenance doses of the target drug every two weeks for at least about 2 weeks; or, 4) Administer maintenance doses of the target drug once a week for at least about 1 week, followed by Administer the seventh dose of the target drug once weekly for at least about 1 week, followed by administering the eighth dose of the target drug once per week for at least about 2 weeks; Preferably, the maintenance dose is selected from about 0.5 mg to about 10.0 mg, or about 1.0 mg to about 8.0 mg; preferably about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 4.5 mg, about 6.0 mg or about 8.0 mg; Preferably, the seventh dose and the eighth dose are independently selected from about 0.5 mg to about 10.0 mg, about 1.0 mg to about 5.0 mg, or about 2.0 mg to about 3.0 mg; preferably about 2.0 mg or about 3.0 mg.

10. The method according to any one of claims 1 to 9, wherein: The second treatment period includes the following regimen: e) administering about 3.0 mg of the target drug once a week for at least about 2 weeks, followed by f) administering about 3.0 mg of the target drug once every two weeks for at least about 4 weeks; or, e) administering about 4.5 mg of the target drug once a week for at least about 2 weeks, followed by f) administering about 4.5 mg of the target drug once every two weeks for at least about 4 weeks; or, e) administering about 6.0 mg of the target drug once a week for at least about 2 weeks, followed by f) administering about 6.0 mg of the target drug once every two weeks for at least about 4 weeks; or, e) administering about 1.0 mg of the target drug once a week for at least about 4 weeks; or, e) administering about 2.0 mg of the target drug once a week for at least about 4 weeks; or, e) administering about 3.0 mg of the target drug once a week for at least about 4 weeks; or, e) administering about 4.0 mg of the target drug once a week for at least about 4 weeks; or, e) administering about 4.5 mg of the target drug once a week for at least about 4 weeks; or, e) administering about 6.0 mg of the target drug once a week for at least about 4 weeks; or, e) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by g) administering about 2.0 mg of the drug of interest once a week for at least about 2 weeks, followed by h) administering about 3.0 mg of the drug of interest once per week for at least about 4 weeks.

11. The method according to any one of claims 1 to 10, wherein: The second treatment period includes the following regimen: e) administering about 3.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks, followed by f) administering about 3.0 mg of the target drug once every two weeks for at least about 4 weeks, such as about 20 weeks; or, e) administering about 4.5 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks, followed by f) administering about 4.5 mg of the target drug once every two weeks for at least about 4 weeks, such as about 20 weeks; or, e) administering about 6.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks, followed by f) administering about 6.0 mg of the target drug once every two weeks for at least about 4 weeks, such as about 20 weeks; or, e) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks; or, e) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks, about 24 weeks, or about 28 weeks; or, e) administering about 3.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks, about 28 weeks; or, e) administering about 4.0 mg of the target drug once a week for at least about 4 weeks, such as about 24 weeks or about 28 weeks; or, e) administering about 4.5 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks or about 28 weeks; or, e) administering about 6.0 mg of the target drug once a week for at least about 4 weeks, such as about 24 weeks or about 28 weeks; or, e) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks, followed by g) administering about 2.0 mg of the target drug once a week for at least about 4 weeks, such as about 4 weeks, followed by h) administering about 3.0 mg of the drug of interest once a week for at least about 4 weeks, such as about 16 weeks.

12. The method according to any one of claims 1 to 11, comprising any of the following schemes: (1) administering about 0.5 mg of the target drug once a week for at least about 2 weeks, followed by About 1.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 1.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by administering about 3.0 mg of the target drug once a week for at least about 4 weeks; (2) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by administering about 3.0 mg of the target drug once every two weeks for at least about 4 weeks; (3) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by administering about 3.0 mg of the target drug once a week for at least about 4 weeks; (4) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.5 mg of the target drug is administered once a week for at least about 2 weeks, followed by administering about 4.5 mg of the target drug once every two weeks for at least about 4 weeks; (5) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by administering about 4.5 mg of the target drug once weekly for at least about 4 weeks; (6) administering about 1.5 mg of the target drug once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 4.5 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 6.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by administering about 6.0 mg of the target drug once every two weeks for at least about 4 weeks; (7) administering about 1.5 mg of the target drug once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 4.5 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by administering about 6.0 mg of the target drug once per week for at least about 4 weeks; (8) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 1.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by administering about 1.0 mg of the target drug once a week for at least about 4 weeks; (9) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by administering about 2.0 mg of the target drug once a week for at least about 4 weeks; (10) administering about 1.5 mg of the target drug once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by administering about 4.5 mg of the target drug once weekly for at least about 4 weeks; (11) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by administering about 4.0 mg of the target drug once per week for at least about 4 weeks; (12) administering about 1.0 mg of the target drug once a week for at least about 2 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 4.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 5.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 6.0 mg of the target drug is administered once a week for at least about 2 weeks, followed by About 6.0 mg of the drug of interest is administered once per week for at least about 4 weeks.

13. The method according to any one of claims 1 to 12, comprising any one of the following schemes: (1) administering about 0.5 mg of the target drug once a week for at least about 4 weeks, followed by About 1.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 20 weeks, followed by About 1.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 8 weeks, followed by About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by administering about 3.0 mg of the target drug once a week for at least about 4 weeks, such as about 16 weeks; (2) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 16 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 8 weeks, followed by administering about 3.0 mg of the target drug once every two weeks for at least about 4 weeks, such as about 20 weeks; (3) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 16 weeks, followed by administering about 3.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks or about 28 weeks; (4) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.5 mg of the target drug is administered once weekly for at least about 12 weeks, followed by About 4.5 mg of the target drug is administered once a week for at least about 4 weeks, such as about 8 weeks, followed by administering about 4.5 mg of the target drug once every two weeks for at least about 4 weeks, such as about 20 weeks; (5) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.5 mg of the target drug is administered once a week for at least about 4 weeks, such as about 12 weeks, followed by administering about 4.5 mg of the target drug once a week for at least about 4 weeks, such as about 28 weeks; (6) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 6.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 12 weeks, followed by About 6.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 8 weeks, followed by administering about 6.0 mg of the target drug once every two weeks for at least about 4 weeks, such as about 20 weeks; (7) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.5 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 6.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 12 weeks, followed by administering about 6.0 mg of the target drug once a week for at least about 4 weeks, such as about 28 weeks; (8) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 1.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 20 weeks, followed by administering about 1.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks; (9) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 2.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 20 weeks, followed by administering about 2.0 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks, about 24 weeks, or about 28 weeks; (10) administering about 1.5 mg of the target drug once a week for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.5 mg of the target drug is administered once a week for at least about 4 weeks, such as about 16 weeks, followed by administering about 4.5 mg of the target drug once a week for at least about 4 weeks, such as about 8 weeks; (11) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.0 mg of the target drug is administered once a week for at least about 4 weeks, such as about 12 weeks, followed by administering about 4.0 mg of the target drug once a week for at least about 4 weeks, such as about 28 weeks; (12) administering about 1.0 mg of the target drug once a week for at least about 4 weeks, followed by About 2.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 3.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 4.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 5.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 6.0 mg of the target drug is administered once weekly for at least about 4 weeks, followed by About 6.0 mg of the drug of interest is administered once a week for at least about 4 weeks, such as about 24 weeks.

14. The method according to any one of claims 1 to 13, wherein: The target drug comprises a GLP-1 analogue having the structure shown below or a pharmaceutically acceptable salt thereof, 15. The method according to any one of claims 1 to 14, wherein: The metabolic disease is obesity or being overweight.

16. A method for improving weight management in a subject in need thereof, comprising administering to the subject a drug of interest according to the method of any one of claims 1-13, in, The target drug is a GLP-1 analog or a pharmaceutically acceptable salt thereof comprising the structure shown below, H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

17. A method for improving glycemic control in a subject in need thereof, comprising administering to the subject a target drug according to the method of any one of claims 1 to 13, in, The target drug is a GLP-1 analog or a pharmaceutically acceptable salt thereof comprising the structure shown below, H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

18. A method for improving blood lipid control in a subject in need thereof, comprising administering a target drug to the subject according to the method of any one of claims 1 to 13, in, The target drug is a GLP-1 analog or a pharmaceutically acceptable salt thereof comprising the structure shown below, H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2.

19. The method according to any one of claims 1 to 18, wherein: The metabolic disease is diabetes, preferably type 2 diabetes.

20. A method for treating type 2 diabetes in a subject in need thereof, comprising administering a target drug to the subject according to the method of any one of claims 1 to 13, in, The target drug is a GLP-1 analog or a pharmaceutically acceptable salt thereof comprising the following structure: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2, Wherein, the type 2 diabetes subject is at least one of the following: 1) Patients who are not effectively treated with lifestyle intervention alone; 2) Those who still have poor response to metformin or metformin combined with SGLT2 inhibitors 3) HbA1c ≥ 7.5% and / or HbA1c ≤ 11%; 4) BMI ≥ 22 kg / m 2 and / or BMI ≤ 40.0 kg / m 2 .

21. The method according to claim 19 or 20, wherein: The subject is also administered metformin, or metformin and an SGLT2 inhibitor.

22. The method according to any one of claims 19 to 21, wherein: The method improves or reduces at least one of the following indicators of the subject: 1) HbA1c; 2) the proportion of subjects with HbA1c <7.0%, HbA1c ≤6.5%, or HbA1c <5.7%; 3) Fasting plasma glucose, serum insulin, and C-peptide 4) plasma glucose, serum insulin, and C-peptide 2 h after a mixed meal; 5) Pancreatic β-cell function and insulin resistance; 6) Average 7-point self-test of blood sugar; 7) Weight, waist circumference, BMI; 8) the proportion of subjects with a weight loss of ≥5%, ≥10%, or ≥15%; 9) Proportion of subjects with HbA1c < 7.0% and weight loss ≥ 5% 10) blood lipids, preferably the blood lipids include one or more of TC, LDL-C, HDL-C and TG; 11) Blood pressure, preferably the blood pressure includes systolic pressure and / or diastolic pressure.