GIP / GLP1 for use in therapy

Abstract

The present invention provides a method for improving glycemic control in a patient in need thereof, the method comprising administering tirzepatide, or a pharmaceutically acceptable salt thereof, to the patient, wherein the patient has not been able to achieve the patient's HbA1c goal using GLP-1 RA therapy.The present invention provides a method for improving weight control in a patient in need thereof, the method comprising administering tirzepatide, or a pharmaceutically acceptable salt thereof, to the patient, wherein the patient has not been able to achieve the patient's weight management goal using GLP-1 RA therapy.

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and more particularly, to a novel method for improving glycemic control in a patient in need thereof, who has not been able to achieve their diabetes treatment goals using a glucagon-like peptide-1 receptor agonist (GLP-1 RA). [Background technology]

[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. In type 2 diabetes (T2D), the combined effects of impaired insulin secretion and insulin resistance are associated with elevated blood glucose levels. While currently approved doses of GLP-1 RA therapy enable the majority of patients to achieve their glycemic goals (with or without the use of other concomitant medications for T2D), a significant number of patients receiving currently approved therapies, including GLP-1 RA therapy, liraglutide, semaglutide, and dulaglutide, do not achieve their glycemic control goals (e.g., Stark Casagrande et al. The prevalence of meeting A1c, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36(8):2271-2279). Therefore, there remains a significant medical need to provide enhanced efficacy of medications while maintaining an acceptable overall benefit / risk profile.

[0003] Patients may be unable to achieve their HbA1c target levels despite receiving GLP-1 RA treatment. Patients may require additional chronic weight management if patients receiving GLP-1 RA treatment are unable to reach their target weight. The present invention provides a treatment option for such patients who are unable to achieve their HbA1c treatment goals despite using appropriate GLP-1 RA treatment. The present invention provides a treatment option for such patients who are unable to achieve their weight loss goals despite using appropriate GLP-1 RA treatment.

[0004] The approved label for tirzepatide requires a 4-week initial dosing regimen using a 2.5 mg dose once weekly. Therefore, several months of treatment may be required to achieve the desired dose for a particular patient. A dosing regimen that provides even more rapid achievement of the desired maximum dose with acceptable patient comfort and / or reduced gastrointestinal effects is desired.

[0005] U.S. Patent No. 9,474,780 generally describes compositions containing GIP and GLP-1 receptor agonists administered parenterally, generally disclosing a wide dosage range of up to about 30 mg per person per week. U.S. Patent No. 9,474,780 discloses the use of GIP / GLP1 coagonists for treating diabetes, obesity, and other conditions. U.S. Patent No. 9,474,780 describes and claims tirzepatide, which has been approved by the U.S. Food and Drug Administration for use in the treatment of type 2 diabetes as an adjunct to diet and exercise.

[0006] Dulaglutide, the active ingredient in Trulicity®, is a GLP-1 RA approved for use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (T2D). Dulaglutide is used to treat many T2D patients, resulting in significant reductions in HbA1c with a low risk of hypoglycemia and weight loss. Dulaglutide is a well-known GLP-1 RA.

[0007] Semaglutide, the active ingredient in Ozempic®, Rybelsis®, and Wegovy®, respectively, is a GLP-1 RA approved for use as an adjunct to diet and exercise to improve glycemic control in patients with T2D. Similarly, semaglutide is a well-known GLP-1 RA.

[0008] Despite the improvements provided by GLP-1 RA treatment, certain patients remain unable to achieve their HbA1c treatment goals. There is a need for additional treatment options to provide the desired glycemic control, evidenced by further reductions in HbA1c, and / or weight loss, while maintaining an acceptable profile of safety and adverse events. There is also a need for treatment options for patients who are unable to achieve metabolic syndrome goals using GLP-1 RAs, including administering tirzepatide for conditions selected from chronic kidney disease, atherosclerosis, NAFLD, and NASH.

[0009] In another embodiment, a method for treating a patient who is receiving GLP-1 RA treatment but is unable to achieve their HbA1c goals comprises administering tirzepatide, or a pharmaceutically acceptable salt thereof. In one embodiment, tirzepatide is administered for at least 20 weeks. In another embodiment, a method for improving chronic weight control in a patient in need thereof, wherein the patient is unable to achieve their weight loss goals using GLP-1 RA treatment, and comprises administering tirzepatide, or a pharmaceutically acceptable salt thereof, to the patient in need thereof. In certain embodiments, the GLP-1 RA is 0.75 mg of dulaglutide once weekly. In certain embodiments, the GLP-1 RA is 1.5 mg of dulaglutide once weekly. In certain embodiments, the GLP-1 RA is 3.0 mg of dulaglutide once weekly. In certain embodiments, the GLP-1 RA is 4.5 mg of dulaglutide once weekly. In certain embodiments, the GLP-1 RA is 0.75 mg of dulaglutide. In certain embodiments, the GLP-1 RA is semaglutide. In one embodiment, the GLP-1 RA is 7 mg of oral semaglutide once daily. In one embodiment, the GLP-1 RA is 14 mg of oral semaglutide once daily. In certain embodiments, the GLP-1 RA is 1.0 mg of semaglutide once weekly. In certain embodiments, the GLP-1 RA is 2.0 mg of semaglutide once weekly. In certain embodiments, the GLP-1 RA is 2.4 mg of semaglutide administered once weekly. In certain embodiments, the GLP-1 RA is 1.4 mg of liraglutide. In certain embodiments, the GLP-1 RA is 1.8 mg of liraglutide. In certain embodiments, the GLP-1 RA is administered within one week before the start of tirzepatide administration. In certain embodiments, the GLP-1 RA is administered within two weeks before the start of tirzepatide administration. In certain embodiments, the GLP-1 RA is administered within three weeks after the start of tirzepatide administration. In certain embodiments, the GLP-1 RA is administered within one month after the start of tirzepatide administration.

[0010] Furthermore, the once-weekly dose of tirzepatide can be administered for more than about 4 weeks. In certain embodiments, if additional glycemic control is needed, the dose of tirzepatide can be increased to the next higher dose contemplated herein. In certain embodiments, the dose of tirzepatide is increased by 2.5 mg for at least 4 weeks. As used herein, the "tirzepatide starting dose" refers to the initial dose of tirzepatide administered to a patient in need of tirzepatide. The tirzepatide starting dose according to the dosing herein can be a 5 mg dose of tirzepatide or a pharmaceutically acceptable salt thereof once weekly. The tirzepatide starting dose can be 2.5 mg of tirzepatide or a pharmaceutically acceptable salt thereof once weekly.

[0011] In another aspect, the present invention provides a method for treating a patient who is unable to achieve HbA1c targets despite at least three months of treatment with a GLP-1 RA, comprising administering to the patient a once-weekly tirzepatide dose of about 5.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about four weeks.In another aspect, the present invention provides a method for treating a patient who has an HbA1c of 6.5-9% despite at least three months of treatment with a GLP-1 RA, comprising administering to the patient a once-weekly tirzepatide dose of about 5.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about four weeks.

[0012] In another aspect, the present invention provides a method of treating a patient who is unable to achieve HbA1c targets despite treatment with a GLP-1 RA for at least 6 months, comprising administering to the patient a once-weekly tirzepatide dose of about 5.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0013] In another aspect, the invention provides a method of treating type 2 diabetes in a patient in need thereof, wherein the patient is failing to achieve HbA1 targets despite treatment with a GLP-1 RA; a) administering to the patient a once-weekly tirzepatide dose of about 2.5 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter a) administering to the patient a once-weekly tirzepatide dose of about 5.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter b) administering to said patient a once-weekly tirzepatide dose of about 7.5 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter c) administering to said patient a once-weekly tirzepatide dose of about 10.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter d) administering to said patient a once-weekly tirzepatide dose of about 12.5 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter e) administering to said patient a once-weekly tirzepatide dose of about 15.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0014] In this embodiment of the invention, dosing proceeds as described above in the previous paragraph, however, the dosing of 2.5 mg of tirzepatide, or a pharmaceutical salt thereof, once weekly is omitted so that the initial tirzepatide dose is 5 mg once weekly.

[0015] The present invention further provides a method for improving glycemic control in a patient in need thereof, wherein the patient is unable to achieve the patient's HbA1c goal using a GLP-1 RA, a) administering to the patient a once-weekly tirzepatide dose of about 2.5 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter b) administering to said patient a once-weekly tirzepatide dose of up to about 15.0 mg of tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0016] Another embodiment is a method of improving glycemic control in a patient in need thereof, wherein the patient is unable to achieve HbA1c targets using a GLP-1 RA; a) administering to said patient a once-weekly tirzepatide dose of about 5.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0017] Another embodiment is a method of improving glycemic control in a patient in need thereof, wherein the patient is unable to achieve HbA1c targets using a GLP-1 RA; a) administering to said patient a once-weekly tirzepatide dose of about 20.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof.

[0018] Another embodiment is a method of improving glycemic control in a patient in need thereof, wherein the patient is unable to achieve HbA1c targets using a GLP-1 RA; a) administering to said patient a once-weekly tirzepatide dose of about 25.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof.

[0019] In yet another aspect, the present invention provides a method for improving weight control in a patient in need thereof, wherein the patient is unable to achieve weight loss goals using a GLP-1 RA, a) administering to the patient a once-weekly tirzepatide dose of about 2.5 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter b) administering to said patient a once-weekly tirzepatide dose of up to about 15.0 mg of tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0020] In yet another aspect, the present invention provides a method for improving weight control in a patient in need thereof, wherein the patient is unable to achieve weight loss goals using a GLP-1 RA, a) administering to the patient a once-weekly tirzepatide dose of about 2.5 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, thereafter b) administering to said patient a weekly tirzepatide dose of up to about 20.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof.

[0021] In yet another aspect, the present invention provides a method for improving weight control in a patient in need thereof, wherein the patient is unable to achieve weight loss goals using a GLP-1 RA, a) administering to the patient a once-weekly dose of about 2.5 mg of tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, followed by b) administering to said patient a weekly tirzepatide dose of up to about 25.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof.

[0022] In yet another aspect, the present invention provides a method for improving weight control in a patient in need thereof, wherein the patient is unable to achieve weight loss goals using a GLP-1 RA, c) administering to the patient an initial weekly tirzepatide dose of about 5.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0023] In another aspect, the present invention provides a method for curing, inducing remission of, or preventing diabetes in a patient in need thereof, wherein the patient has not been able to achieve such cure, remission, or prevention using a GLP-1 RA, comprising administering to the patient once weekly tirzepatide.In another aspect, the present invention provides a method for curing, inducing remission of, or preventing diabetes in a patient in need thereof, wherein the patient has not been able to achieve such cure, remission, or prevention using a GLP-1 RA, comprising administering to the patient once weekly 5.0 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

[0024] The present invention relates to the use of tirzepatide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating type 2 diabetes in a patient in need thereof, wherein the patient has been unable to achieve type 2 diabetes goals using a GLP-1 RA; a) administering tirzepatide to said patient once weekly.

[0025] In another aspect, the present invention provides use of tirzepatide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for improving glycemic control in a patient in need thereof, wherein the patient is unable to achieve the patient's HbA1c goal using a GLP-1 RA, comprising administering tirzepatide once weekly to the patient.

[0026] Another embodiment is the use of tirzepatide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for improving weight control in a patient in need thereof, wherein the patient has not been able to achieve the patient's weight loss goals using dulaglutide; a) administering to the patient a once-weekly dose of about 2.5 mg of tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks, followed by b) administering to said patient a once-weekly tirzepatide dose of about 15.0 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0027] Another embodiment is the use of tirzepatide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for improving weight control in a patient in need thereof, wherein the patient has not been able to achieve the patient's weight loss goals using GLP-1 RA therapy; a) administering to said patient a once-weekly tirzepatide dose of about 2.5 mg tirzepatide, or a pharmaceutically acceptable salt thereof, for a minimum of about 4 weeks.

[0028] In another aspect, the present invention provides use of tirzepatide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for improving weight control in a patient in need thereof, wherein the patient has not been able to achieve the patient's weight loss goals using GLP-1 RA therapy, comprising administering an initial tirzepatide dose of about 5.0 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

[0029] Nonalcoholic fatty liver disease (NAFLD) is a liver disease characterized by the accumulation of fat in the liver of affected patients. Patients suffering from NAFLD may consume little or no alcohol, and in one embodiment, the patient does not have comorbid diabetes. NAFLD is the leading cause of liver disease worldwide. Younossi et al. Global epidemiology of nonalcoholic fatty liver disease - Meta-analytic assessment of prevalence, incidence, and outcomes; Hepatology (July 2016) 64:1; 73-84. Nonalcoholic steatohepatitis (NASH) is a type of NAFLD with a constellation of etiologies exhibiting macrovesicular hepatic steatosis, inflammation, hepatocyte ballooning, and fibrosis.

[0030] NAFLD and NASH are progressive diseases characterized by the development of liver fibrosis as NAFLD progresses to NASH.

[0031] In one embodiment, a method for treating type 2 diabetes in a patient receiving basal insulin therapy, comprising administering an effective amount of tirzepatide for at least 4 weeks and reducing the basal insulin dose. In one embodiment, a method for treating type 2 diabetes in a patient who has been diagnosed with type 2 diabetes for at least 5 years and is currently receiving basal insulin therapy, comprising administering an effective amount of tirzepatide and reducing the basal insulin dose.

[0032] In a clinical study, patients with long-standing type 2 diabetes already using basal insulin were randomized to receive tirzepatide (TZP) 5 mg, 10 mg, or 15 mg for 52 weeks of treatment. The median basal insulin dose at the start of treatment was 46 U / day. At week 52, patients on TZP experienced significant reductions in HbA1c (-1.92%, -2.15%, and -2.3% for tirzepatide 5 mg, 10 mg, and 15 mg, respectively), with 58%, 71.9%, and 72.8% of patients achieving an HbA1c goal of less than 7%. Patients did not need to add additional basal insulin; rather, they observed substantially less basal insulin use compared with treatment status. The median basal insulin doses at week 52 were 20.3, 12.0, and 8.3 U / day for TZP 5 mg, 10 mg, and 15 mg, respectively. In addition, 8%, 15% and 21% of patients were completely weaned off basal insulin at 52 weeks for TZP 5 mg, 10 mg and 15 mg, respectively.

[0033] The present invention provides a method for treating NAFLD, comprising administering an effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient has not been able to resolve their NAFLD using GLP-1 RA therapy.The present invention provides a method for treating NASH, comprising administering an effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient has not been able to resolve their NASH using GLP-1 RA therapy.

[0034] Chronic kidney disease ("CKD") is defined as an abnormality in the structure or function of the kidneys that exists for three months and affects the patient's health.

[0035] The present invention provides a method for treating CKD, comprising administering an effective amount of tirzepatide to a patient in need thereof, wherein the patient has not been able to resolve their CKD using GLP-1 RA treatment.

[0036] U.S. Patent No. 9,474,780 teaches that tirzepatide is useful for treating diabetes, where "treating" includes arresting, slowing, halting, or reversing the progression or severity of existing symptoms or disorders. Despite advances in diabetes treatment, many patients undergoing such treatment fail to achieve their glycemic control or HbA1c goals. As used herein, the term "GLP-1 RA" refers to glucagon-like peptide-1 receptor agonist therapy, the pharmacological activity of which is primarily due to agonism at the GLP-1 receptor. For the avoidance of doubt, the term GLP-1 RA does not include tirzepatide, a dual GIP:GLP-1 agonist. In one embodiment, GLP-1 RA refers to a GLP-1 RA therapy approved by the U.S. FDA or a corresponding regulatory agency for use in the treatment of T2D. For example, GLP-1 RAs include, but are not limited to, semaglutide, dulaglutide, liraglutide, and other oral and / or subcutaneous GLP-1 RA medications approved for administration in the treatment of diabetes and / or weight management. In certain embodiments, dulaglutide is a preferred GLP-1 RA. In certain embodiments, semaglutide is a preferred GLP-1 RA. In certain embodiments, liraglutide is a preferred GLP-1 RA. As used herein, it is intended that GLP-1 RAs be administered according to their respective FDA-approved label instructions.

[0037] In certain embodiments, tirzepatide is administered for at least 4 weeks. In certain embodiments, tirzepatide is administered for at least 20 weeks. In certain embodiments, tirzepatide is administered for at least 6 months. In certain embodiments, tirzepatide is administered for at least 1 year. In certain embodiments, a GLP-1 RA is administered within 1 week of the first tirzepatide dose. In certain embodiments, a GLP-1 RA is co-administered with tirzepatide.

[0038] As used herein, the terms "diabetic drug," "diabetic medication," and the like refer to drugs approved by relevant regulatory authorities for use in glycemic control or the treatment of type 2 diabetes. In one embodiment, the patient continues administration of the diabetes medication concurrently with administration of tirzepatide. In one embodiment, the patient maintains the patient's HbA1c target level for at least one month without further administration of tirzepatide. In one embodiment, a patient who has failed to achieve HbA1c targets using GLP-1 RA treatment maintains their glycemic targets for at least six months after the patient's last treatment with tirzepatide. In one embodiment, the tirzepatide dose is administered within two weeks of the last GLP-1 RA dose. In one embodiment, the tirzepatide dose is administered within one week of the last GLP-1 RA dose. In one embodiment, tirzepatide is administered within four days of the last GLP-1 RA dose. In one embodiment, tirzepatide is administered concurrently with a GLP-1 RA.

[0039] In one embodiment, tirzepatide is administered to a patient in need of treatment for addictive behavior. In one embodiment, there is provided a method for treating addictive behavior, comprising administering an effective amount of tirzepatide to a patient in need thereof. The term "additive behavior" means that the patient has a compulsive urge to use a substance or perform a behavior. Such addictive behavior continues despite harmful consequences. Urges to use substances may include, but are not limited to, alcohol, drugs, nicotine, and excessive food. Urges to perform behaviors may include, but are not limited to, confusion, gambling, and other undesirable mood-altering behaviors.

[0040] The dose of tirzepatide of the present invention may have a specific concentration of 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, and 50 mg / mL. Such compositions may be provided in a pre-filled syringe. Such pre-filled syringes may be useful for administering 0.5 milliliters of such compositions per dose per patient. The dose of the present invention is typically administered subcutaneously. The dose is typically administered using a pre-filled disposable pen, a reusable pen, or an automatic pen injector. In one embodiment, the device is an automatic injection device as claimed in U.S. Patent No. 8,734,394.

[0041] As used herein, "tirzepatide" refers to the GIP / GLP1 dual agonist peptide described in U.S. Patent No. 9,474,780 and described by CAS Registry Number: 2023788-19-2.

[0042] Tirzepatide is described in Example 1 of U.S. Pat. No. 9,474,780 and has the following sequence: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, and K at position 20 is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO—(CH2) 18 It is chemically modified by conjugation of the K side chain with -CO2H to the epsilon-amino group, and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).

[0043] As used herein, the term "administering" means administration by a nurse, healthcare provider, patient, or any other individual, including self-administration. As used herein, administering can include prescribing, dispensing, or assisting in any manner with delivery, as performed by a healthcare professional.

[0044] As used herein, "pharmaceutically acceptable salts" are well known to those skilled in the art. In one embodiment, the pharmaceutically acceptable salt is tirzepatide trifluoroacetate salt. In one embodiment, tirzepatide is administered as a salt free form.

[0045] As used herein, the term "biomarker" refers to a laboratory measurement that reflects the activity of a disease process. Biomarkers can be used to diagnose a disease or condition and usually correlate quantitatively (directly or inversely) with disease progression. In a clinical trial setting, a biomarker is a measure of the effectiveness of a particular treatment and may correlate with an actual clinical endpoint, but not necessarily in an exact relationship; i.e., the biomarker is a surrogate measure of the clinical endpoint.

[0046] As used herein, the terms "treatment," "treat," "treating," and the like are meant to include slowing or attenuating the progression of a disease or disorder. The terms also include alleviating, ameliorating, or alleviating one or more symptoms of a disorder or condition, even if the disorder or condition is not eliminated or its progression is not slowed. As used herein, an HbA1c target is an HbA1c biomarker level to be achieved by a patient, as determined by a physician by assessing the patient's condition, age, comorbidities, etc.

[0047] As used herein, "refractory diabetes" means that a patient using GLP-1 RA therapy is unable to achieve their blood glucose or HbA1c goals. This term can also mean that a patient using semaglutide is unable to achieve their blood glucose or HbA1c and / or weight management goals. This term can also mean that a patient using dulaglutide is unable to achieve their blood glucose or HbA1c and / or weight management goals. In one embodiment, the term "improving glycemic control" can mean that the HbA1c reduction using the regimen disclosed herein is greater than would be expected for a patient using a tirzepatide T2D-labeled dosing regimen. In one embodiment, the weight control achieved using the dosing regimen disclosed herein is greater than would be expected for a patient using a tirzepatide T2D-labeled dosing regimen.

[0048] In one embodiment, a patient using the dosing regimen disclosed herein in the treatment of diabetes achieves at least the patient's glycemic control treatment goal, which is maintained upon discontinuation of treatment with tirzepatide and all other diabetes medications. In one embodiment, the patient glycemic goal is an HbA1c of less than about 5.9% HbA1c.

[0049] "Glycemic control" refers to maintaining or reducing a subject's HbA1c level. "Improving" glycemic control refers to reducing HbA1c, and "requiring" "further" glycemic control refers to the need for a reduction in HbA1c. In one embodiment, "requiring further glycemic control" means that the patient is not achieving the patient's HbA1c goal as determined by the patient's physician.

[0050] In one embodiment, a novel dosing regimen for treating patients who are unable to reach their therapeutic goals using GLP-1 RA therapy is a method of using a dosing regimen comprising treating the patient with tirzepatide, a GLP-1 RA and GIP / GLP1 dual agonist peptide, or a pharmaceutically acceptable salt thereof.

[0051] As used herein, "resolving" CKD means that a patient sufficiently achieves biomarker targets that indicate a slowing of progression or improvement in the extent of CKD, as determined by the patient's physician.

[0052] As used herein, "resolving" NASH or "resolving" NAFLD means that a patient achieves a biomarker target that indicates improvement, reduction, and / or slowed progression of NASH or NAFLD, as determined by the patient's physician. In one embodiment, "resolving" NASH or NAFLD means that a liver biopsy shows a reduction in the condition or slowed progression.

[0053] As used herein, "weight management" refers to weight loss. In one embodiment, weight management refers to the management of obesity in an individual. As used herein, "improving" weight management refers to weight loss. In one embodiment, "requiring further weight management" or "requiring further weight loss" means that a patient has not achieved their weight loss goal as determined by their physician for their health. As used herein, "failing to achieve weight loss goal" means that further weight loss is required to achieve a weight loss goal as determined by a healthcare provider. In one embodiment, "failing to achieve weight loss goal" means that a weight loss goal has been achieved, however, weight loss has not been adequately maintained at the target weight as determined by the patient's healthcare provider.

[0054] As used herein, "HbA1c" refers to the level of glycated hemoglobin, which occurs when hemoglobin binds with glucose in the blood. HbA1c levels are a commonly used measure of glycemic control in patients with diabetes, and a decrease in HbA1c levels generally indicates improved glycemic control. In connection with the methods of the present invention, the methods of the present invention result in a decrease in HbA1c. In certain embodiments, HbA1c is reduced compared to the HbA1c level expected from treatment using an FDA-approved tirzepatide dosing regimen. In certain embodiments, the patient's side effect experience is improved compared to the average treatment experience using an FDA-approved tirzepatide dosing regimen.

[0055] As used herein, "patient" or "patients" refers to a mammal in need of treatment for a condition or disorder. In one embodiment, the patient is a human having a disease or condition, and the patient is unable to achieve the patient's treatment goals. In one embodiment, the patient is unable to achieve the patient's HbA1c goals using GLP-1 RA therapy. In one embodiment, the patient is unable to achieve the patient's weight loss goals using GLP-1 RA therapy.

[0056] As used herein, "diabetes treatment goal" refers to the desired HbA1c level and / or weight reduction as determined by a medical professional. As used herein, HbA1c goal refers to the HbA1c level to be achieved as determined by the patient's physician. Treatment goals may vary from patient to patient based on the physician's assessment.

[0057] Biomarkers Clinically relevant biomarkers will be measured in clinical studies to further support the use of tirzepatide to treat CKD in patients who are unable to achieve such biomarker levels using GLP-1 RAs.

[0058] Biomarkers predicting NAFLD will be observed in patients who are unable to achieve such beneficial effects with GLP-1 RAs during clinical studies to demonstrate the beneficial effects of tirzepatide in the treatment of NAFLD. Biomarkers predicting NASH will be observed during clinical trials to demonstrate the beneficial effects of tirzepatide in the treatment of NASH. HbA1c levels will be measured during follow-up in tirzepatide-treated patients who achieve glycemic control goals and discontinue antidiabetic medications to verify diabetes cure in such patients. [Example]

[0059] Example 1 Clinical Dosage Regimen An open-label, single-arm, multicenter, multinational, phase 4 study to evaluate changes in glycemic control when switching directly from a stable dose of a GLP-1 RA to tirzepatide 5 mg in participants with type 2 disease. The study will include 150 subjects.

[0060] The study included a screening period and a 12-week treatment period.

[0061] The primary objective based on the efficacy estimate will be evaluated using the EAS dataset. The primary analysis model for HbA1c measurements over time will be MMRM. The response variable for MMRM will be the change in HbA1c values ​​from baseline obtained at each scheduled post-baseline visit. The independent variables in the MMRM model will be visit, with country as a fixed effect and baseline HbA1c as a covariate. Missing data will be addressed by the MMRM model. No explicit imputation methods for missing data will be used. The P-value obtained for the least squares means for the change from baseline will be used to determine statistical significance for achieving the primary objective.

[0062] As used herein, MMRM means mixed models for repeated measures.

[0063] Efficacy Analysis Set (EAS): This analysis set will be used to estimate the efficacy estimate for the primary objective.

[0064] Data obtained during the treatment period from a population excluding inadvertently enrolled participants, excluding data after permanent discontinuation of treatment or initiation of prohibited medications.

[0065] array SEQ ID NO: 1 Tirzepatide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, and K at position 20 is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO—(CH2) 18 It is chemically modified through conjugation of the K side chain with -CO2H to the epsilon-amino group, and the C-terminal amino acid is amidated as a C-terminal primary amide.

Claims

1. 1. A method of improving glycemic control in a patient in need thereof, wherein the patient is receiving GLP-1 RA treatment, the method comprising administering tirzepatide, or a pharmaceutically acceptable salt thereof, once weekly.

2. 10. The method of claim 1, wherein the patient undergoing GLP-1 RA treatment is unable to achieve the patient's HbA1c treatment goal.

3. 3. The method of claim 1 or 2, wherein the patient HbA1c target is 7.0 or less.

4. The method of any one of claims 1 to 3, wherein the patient HbA1c target is 6.5 or less.

5. The method of any one of claims 1 to 4, wherein the patient HbA1c target is 6.0 or less.

6. The method of any one of claims 1 to 5, wherein the patient HbA1c goal is normoglycemia.

7. 7. The method of any one of claims 1 to 6, wherein the once-weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, and 25 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

8. 8. The method of any one of claims 1 to 7, wherein the once-weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

9. The method according to any one of claims 1 to 8, wherein the initial dose of tirzepatide is 2.5 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

10. The method according to any one of claims 1 to 8, wherein the initial dose of tirzepatide is 5.0 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1 to 10, wherein a once-weekly dose of tirzepatide is administered for at least 4 weeks.

12. The method of any one of claims 1 to 11, wherein the GLP-1 RA is dulaglutide.

13. 13. The method of any one of claims 1 to 12, wherein the GLP-1 RA is 3.0 mg of dulaglutide once weekly.

14. 13. The method of any one of claims 1 to 12, wherein the GLP-1 RA is 1.5 mg of dulaglutide once weekly.

15. 13. The method of any one of claims 1 to 12, wherein the GLP-1 RA is 4.5 mg of dulaglutide once weekly.

16. The method of any one of claims 1 to 11, wherein the GLP-1 RA is semaglutide.

17. 17. The method of claim 16, wherein the once-daily dose of semaglutide is 7 mg.

18. 17. The method of claim 16, wherein the once-daily dose of semaglutide is 14 mg.

19. 17. The method of claim 16, wherein the once weekly dose of semaglutide is 1.0 mg.

20. 17. The method of claim 16, wherein the once weekly dose of semaglutide is 2.0 mg.

21. 17. The method of claim 16, wherein the once weekly dose of semaglutide is 2.4 mg.

22. 22. The method of any one of claims 19 to 21, wherein the weekly dose is administered subcutaneously.

23. The method of any one of claims 1 to 11, wherein the GLP-1 RA is liraglutide.

24. 24. The method of claim 23, wherein the dose of liraglutide is 1.2 mg per day.

25. 24. The method of claim 23, wherein the dose of liraglutide is 1.8 mg per day.

26. The method of any one of claims 1 to 11 or claims 16 to 22, wherein the patient has been treated with semaglutide for a treatment period of at least 6 months prior to administration of tirzepatide, or a pharmaceutically acceptable salt thereof.

27. The method according to any one of claims 1 to 11, wherein the GLP-1 RA is a non-peptide GLP-1 RA.

28. The method of any one of claims 1 to 11, wherein the GLP-1 RA is administered subcutaneously.

29. The method of any one of claims 1 to 11, wherein the GLP-1 RA is administered orally.

30. The patient has a blood pressure of 25 kilograms per square meter (kg / m ２ The method according to any one of claims 1 to 29, wherein the patient has a BMI of 1 or greater.

31. 1. A method of improving glycemic control in a patient, comprising administering once-weekly tirzepatide, or a pharmaceutically acceptable salt thereof, to said patient, wherein said patient has failed to achieve said patient's HbA1c goal with GLP-1 RA treatment.

32. 1. A method of improving weight control in a patient in need thereof, comprising administering once-weekly tirzepatide, or a pharmaceutically acceptable salt thereof, to said patient, wherein said patient has failed to achieve said patient's weight loss goal using GLP-1 RA therapy.

33. 33. The method of claim 32, wherein the patient weight loss goal is 15% of the patient's body weight.

34. 34. The method of claim 32 or 33, wherein the patient weight loss goal is a weight loss of greater than 20% of the patient's body weight.

35. 35. The method of any one of claims 32-34, wherein the patient weight loss goal is a weight loss of greater than 25% of the patient's body weight.

36. 36. The method of any one of claims 32 to 35, wherein the patient weight loss goal is maintained for at least six months.

37. 37. The method of any one of claims 32-36, wherein the once-weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, and 25 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

38. 38. The method of any one of claims 32-37, wherein the once-weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

39. The method of any one of claims 32 to 38, wherein the initial tirzepatide dose is 2.5 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

40. The method of any one of claims 32 to 38, wherein the initial tirzepatide dose is 5.0 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

41. 41. The method of any one of claims 32 to 40, wherein a once-weekly dose of tirzepatide is administered for at least 4 weeks.

42. The method of any one of claims 32 to 41, wherein the GLP-1 RA is dulaglutide.

43. 43. The method of any one of claims 32 to 42, wherein the GLP-1 RA is 3.0 mg of dulaglutide once weekly.

44. 43. The method of any one of claims 32 to 42, wherein the GLP-1 RA is 1.5 mg of dulaglutide once weekly.

45. 43. The method of any one of claims 32 to 42, wherein the GLP-1 RA is 4.5 mg of dulaglutide once weekly.

46. The method of any one of claims 32 to 41, wherein the GLP-1 RA is semaglutide.

47. 47. The method of claim 46, wherein the once daily dose of semaglutide is 7 mg.

48. 47. The method of claim 46, wherein the once daily dose of semaglutide is 14 mg.

49. 47. The method of claim 46, wherein the once weekly dose of semaglutide is 1.0 mg.

50. 47. The method of claim 46, wherein the weekly dose of semaglutide is 2.0 mg.

51. 47. The method of claim 46, wherein the weekly dose of semaglutide is 2.4 mg.

52. 52. The method of any one of claims 49-51, wherein the weekly dose is administered subcutaneously.

53. The method of any one of claims 32 to 41, wherein the GLP-1 RA is liraglutide.

54. 54. The method of claim 53, wherein the dose of liraglutide is 1.2 mg per day.

55. 54. The method of claim 53, wherein the dose of liraglutide is 1.8 mg per day.

56. 53. The method of any one of claims 32 to 41 or claims 46 to 52, wherein the patient is treated with semaglutide for a treatment period of at least 6 months prior to administration of tirzepatide, or a pharmaceutically acceptable salt thereof.

57. The method of any one of claims 32 to 41, wherein the GLP-1 RA is a non-peptide GLP-1 RA.

58. The method of any one of claims 32 to 41, wherein the GLP-1 RA is administered subcutaneously.

59. The method of any one of claims 32 to 41, wherein the GLP-1 RA is administered orally.

60. The patient has a blood pressure of 25 kilograms per square meter (kg / m ２ The method of any one of claims 32 to 59, wherein the patient has a BMI of 10 or greater.

61. 1. An improved method for treating type 2 diabetes in patients who are unable to achieve diabetes treatment goals using GLP-1 RA therapy, the improvement comprising: The improved method comprises administering a once-weekly dose of tirzepatide.

62. 62. The improved method of claim 61, wherein the weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, and 25 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

63. 63. The improved method of claim 61 or 62, wherein the weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

64. 62. The improved method of claim 61, wherein the once weekly dose of tirzepatide is 5 mg.

65. 65. The improved method of any one of claims 61 to 64, wherein the patient continues GLP-1 RA treatment with 5 mg of tirzepatide administered once weekly.

66. 66. The improved method of any one of claims 61-65, wherein the patient discontinues GLP-1 RA treatment about 1 week prior to administering tirzepatide once weekly.

67. 67. The improved method of any one of claims 61 to 66, wherein the patient's type 2 diabetes treatment goal is an HbA1c of less than 7.

5.

68. 67. The improved method of any one of claims 61 to 66, wherein the patient diabetes treatment goal is an HbA1c of less than 7.

0.

69. 67. The improved method of any one of claims 61 to 66, wherein the patient diabetes treatment goal is an HbA1c of less than 6.

5.

70. 70. The improved method of any one of claims 61 to 69, wherein the diabetes treatment goal is a weight loss of more than 15% of the patient's body weight.

71. 71. The improved method of any one of claims 61 to 70, wherein the diabetes treatment goal is a weight loss of more than 20% of the patient's body weight.

72. 72. The improved method of any one of claims 61 to 71, wherein the diabetes treatment goal is a weight loss of more than 25% of the patient's body weight.

73. 73. The method of any one of claims 61 to 72, wherein the GLP-1 RA is dulaglutide.

74. 73. The method of any one of claims 61 to 72, wherein the GLP-1 RA is semaglutide.

75. 73. The method of any one of claims 61 to 72, wherein the GLP-1 RA is liraglutide.

76. 1. A method of treating diabetes in a patient in need thereof, comprising administering once-weekly tirzepatide, or a pharmaceutically acceptable salt thereof, to said patient, wherein said patient has failed to achieve said patient's HbA1c goal using GLP-1 RA therapy.

77. 77. The method of claim 76, wherein the patient HbA1c target is 7.0 or less.

78. 78. The method of claim 76 or 77, wherein the patient HbA1c target is 6.5 or less.

79. 79. The method of any one of claims 76 to 78, wherein the patient HbA1c goal is 6.0 or less.

80. 80. The method of any one of claims 76-79, wherein the patient HbA1c goal is normoglycemia.

81. 81. The method of any one of claims 76-80, wherein the weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, and 25 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

82. 82. The method of any one of claims 76-81, wherein the weekly dose of tirzepatide is selected from the group consisting of 2.5 mg, 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

83. 83. The method of any one of claims 76 to 82, wherein the initial tirzepatide dose is 2.5 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

84. 83. The method of any one of claims 76 to 82, wherein the initial tirzepatide dose is 5.0 mg of tirzepatide, or a pharmaceutically acceptable salt thereof.

85. 85. The method of any one of claims 76 to 84, wherein a once-weekly dose of tirzepatide is administered for at least 4 weeks.

86. The method of any one of claims 76 to 85, wherein the GLP-1 RA is dulaglutide.

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