Chilzepatide for use in the treatment of T2D

Abstract

The present invention provides a method for treating or preventing type 2 diabetes in patients with low HOMA2-B using tilzepatide as a first-line pharmaceutical treatment for diabetes. A method is also provided for treating patients with long-term type 2 diabetes using tilzepatide and reduction or elimination of basal insulin therapy, such treatment being continued for at least 26 weeks.

Description

Technical Field

[0001] The present invention relates to the field of medicine. More specifically, the present invention is a new method for managing glycemic control in patients with long-term type 2 diabetes who require basal insulin therapy to manage glycemic control, the method comprising administering to such patients, once weekly for at least 52 weeks, an effective amount of tildepepide or a pharmaceutically acceptable salt thereof. Another aspect relates to treating or preventing type 2 diabetes in patients having a HOMA-2B of less than 1, which comprises administering a therapeutically effective amount of tildepepide, wherein tildepepide is a first-choice type 2 diabetes treatment.

[0002] The present disclosure relates to methods of using tildepepide to prevent or treat type 2 diabetes, which is characterized by poor pancreatic beta cell function (HOMA2-B quartile 1, c-peptide) in human subjects. The present disclosure also relates to the administration of tildepepide to such patients for treating or preventing diseases characterized by impaired glycemic control. Some aspects of the present disclosure relate to treating or preventing diseases characterized by impaired glycemic control with poor pancreatic beta cell function in human subjects, wherein the human subject is selected based on the patient's HOMA 2-B (C-peptide) status and / or is treated with tildepepide as a monotherapy for type 2 diabetes. Diseases that can be treated or prevented using tildepepide or the methods disclosed herein include, for example, type 2 diabetes and conditions in which glycemic control is beneficial. In some embodiments, the present disclosure relates to preserving pancreatic beta cell function in a subject, as indicated by HOMA 2-B (C-peptide). In some embodiments, the present disclosure relates to selecting patients to restore or improve pancreatic beta cell function in a human subject.

Background Art

[0003] Diabetes mellitus is a chronic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In type 2 diabetes (T2D), a combined effect of impaired insulin secretion and insulin resistance is associated with elevated blood glucose levels. Insulin therapy remains basal and is often a last resort for patients with long-standing type 2 diabetes and uncontrolled hyperglycemia. Insulin is generally initiated with basal insulin and gradually escalated. However, due to the progressive loss of beta-cell function, many patients eventually require augmentation of treatment using meal insulin. Basal bolus insulin regimens (i.e., once daily basal insulin and three daily meal insulin doses) have historically been considered the absolute standard insulin regimen by most treatment guidelines for patients with long-standing type 2 diabetes that is poorly controlled with basal insulin. However, such treatments often involve the need to increase insulin doses and frequently involve complex treatment plans. Such complex insulin treatment plans can be associated with an increased risk of hypoglycemia. There is a need for treatment plans to mitigate the risks associated with basal insulin treatment for type 2 diabetes. In one embodiment, basal insulin therapy is relevant to patients with long-term type 2 diabetes. Therefore, there remains a critical medical need to provide treatment options with an acceptable benefit / risk profile for patients with long-term type 2 diabetes who cannot control their type 2 diabetes with basal insulin. [Overview of the Initiative]

[0004] Therefore, embodiments are provided to address the need for such treatment.

[0005] A method for improving blood glucose control in patients who require improvement in blood glucose control by administering tilzepatide, a) Determining the patient's homeostatic model assessment (HOMA) 2-B state, i. Obtaining or having obtained a biological sample from a patient, ii. The HOMA 2-B evaluation is performed on the sample, or the evaluation is performed, b) If the patient's HOMA 2-B is less than 1 (C-peptide), administer an effective dose of tilzepatide as the first-line treatment for type 2 diabetes, A method in which such treatment is administered for at least 26 weeks.

[0006] A method for improving blood glucose control in patients who require improvement in blood glucose control by administering tilzepatide, a) Determining the patient's Homeostatic Model Assessment (HOMA) 2-B state, i. Obtaining or having obtained a biological sample from a patient, ii. The HOMA 2-B evaluation is performed on the sample, or the evaluation is performed, b) If the patient's HOMA 2-B is less than 1 (C-peptide), administer an effective dose of tilzepatide as the first-line treatment for type 2 diabetes, A method in which such treatment is administered for at least 52 weeks.

[0007] A method for treating or preventing type 2 diabetes in patients with HOMA2-B less than 1, comprising administering a therapeutically effective dose of tilzepatide or a pharmaceutically acceptable salt thereof, wherein tilzepatide is a first-line pharmacotherapy for type 2 diabetes.

[0008] A method for treating or preventing type 2 diabetes in a patient with HOMA2-B less than 1, comprising administering a therapeutically effective dose of tilzepatide or a pharmaceutically acceptable salt thereof, wherein tilzepatide is a first-line pharmacotherapy for type 2 diabetes, and such treatment is administered for at least 26 weeks. [Modes for carrying out the invention]

[0009] The present invention provides a treatment option for patients with long-term type 2 diabetes who are unable to achieve blood glucose control targets using basal insulin. Furthermore, there is a need for a treatment that provides blood glucose control therapy for patients with long-term type 2 diabetes, and such treatment provides blood glucose control without the use of insulin.

[0010] U.S. Patent No. 9474780 generally describes compositions containing GIP and GLP-1 receptor agonists administered via parenteral routes and generally discloses a broad dose range of up to approximately 30 mg per person per week. U.S. Patent No. 9474780 discloses the use of GIP / GLP1 coagonists for the treatment of diabetes, obesity, and other conditions. U.S. Patent No. 9474780 describes and claims tilzepatide. Tilzepatide is 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.

[0011] In another aspect, the present invention provides the use of tilzepatide or a pharmaceutically acceptable salt thereof in the manufacture of a drug for improving blood glucose control in a patient who is required to have improved blood glucose control and who is determined to have low HOMA-2B.

[0012] U.S. Patent No. 9,474,780 teaches that tilzepatide is useful in the treatment of diabetes, and “treatment” includes slowing, reducing, stopping, or reversing the progression or severity of existing symptoms or impairments. Despite advances in the treatment of diabetes, many patients receiving such treatment are unable to reach their blood glucose control targets or HbA1c targets. As used herein, the term “insulin” means basal insulin or mealtime insulin as recognized by those skilled in the art and approved by regulatory authorities. As used herein, “basal insulin” means long-acting insulin, such as insulin glargine. As used herein, “mealtime insulin” means short-acting insulin or rapid-acting insulin, such as insulin lispro. The term “insulin” is intended to encompass both basal insulin and mealtime insulin. As used herein, insulin is intended to be administered in accordance with its respective FDA or similar regulatory authority approved label instructions.

[0013] In certain embodiments, tilzepatide is administered for at least 26 weeks. In certain embodiments, tilzepatide is administered for at least 52 weeks. In certain embodiments, tilzepatide is administered for at least 6 months. In certain embodiments, tilzepatide is administered for at least 1 year.

[0014] As used herein, "HOMA-2B" refers to the homeostasis model evaluation 2B c-peptide. As used herein, "low HOMA-2B" refers to a value less than approximately 1. In one embodiment, "low HOMA-2B" means that HOMA-2B is in the lowest quartile relative to the standard population.

[0015] As used herein, terms such as “diabetes drug” and “diabetes medication” mean drugs approved by the relevant regulatory authority for use in blood glucose control or the treatment of type II diabetes. As used herein, “first-line treatment” means the first drug for use in the treatment of type II diabetes that is approved by the relevant regulatory authority for use in blood glucose control or the treatment of type II diabetes.

[0016] In one embodiment, patients with low HOMA-2B are administered tilzepatide or a pharmaceutically acceptable salt thereof as a first-line treatment for glycemic control or type 2 diabetes.

[0017] In one embodiment, the patient maintains their HbA1c target level for at least one month without further insulin administration.

[0018] As used herein, “suspected of type 2 diabetes” means that a patient has at least two known risk factors for type 2 diabetes, such as excessive abdominal fat, obesity, sedentary lifestyle, family history, being over 45 years of age, gestational diabetes, or polycystic ovary syndrome. In one embodiment, “suspected of type 2 diabetes” means that a patient is diagnosed with prediabetes. The typical HbA1c range for prediabetes is about 5.7% to about 6.4%.

[0019] The doses of tilzepatide according to the present invention are likely to have specific concentrations 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 pre-filled syringes. Such pre-filled syringes may be useful for administering 0.5 milliliters of such compositions per patient dose. The doses of the present invention are typically administered subcutaneously. The doses are typically administered using a pre-filled disposable pen, a reusable pen, or an auto-pen injector. In one embodiment, the device is an auto-injector claimed by U.S. Patent No. 8,734,394.

[0020] As used herein, "tilsapanide" means a GIP / GLP1 dual agonist peptide described in U.S. Patent No. 9,474,780 and described by CAS Registry Number: 2023788-19-2.

[0021] Tilsapanide is described in Example 1 of U.S. Patent No. 9,474,780 and has the following sequence: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS, where X1 is Aib, X2 is Aib, the K at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side chain with (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H, and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).

[0022] As used herein, the term "administering" means administration by a nurse, healthcare provider, patient, or any other individual including self-administration. As used herein, administration can include prescribing, dispensing, or assisting delivery in any manner by a medical professional.

[0023] As used herein, "pharmaceutically acceptable salts" are well known to those skilled in the art. In one embodiment, it is a pharmaceutically acceptable salt which is the tilsapanide trifluoroacetate salt. In one embodiment, tilsapanide is administered as salt-free.

[0024] As used herein, the term "biomarker" means a laboratory measurement that reflects the activity of a disease process. Biomarkers are used to diagnose a disease or condition and can typically correlate (either directly or inversely) quantitatively with the progression of the disease. In a clinical trial setting, a biomarker is a measure of the effect of a specific treatment, which may correlate with the actual clinical endpoint but not necessarily with an exact relationship, i.e., a biomarker is a surrogate measure of the clinical endpoint.

[0025] As used herein, terms such as "treatment", "treating", "treatment of" mean including delaying or attenuating the progression of a disease or disorder. This term includes alleviating, improving, or reducing one or more symptoms of a disorder or condition even if the disorder or condition is not resolved or the progression is not slowed. As used herein, the HbA1c target is the HbA1c biomarker level to be achieved by a patient, which is determined by a physician by evaluating the patient's condition, age, comorbid diseases, etc.

[0026] As used herein, "long-term type 2 diabetes" means a patient diagnosed with type 2 diabetes for at least 13 years. This term may mean that patients using insulin are unable to achieve their blood glucose or HbA1c targets.

[0027] In one embodiment, a patient using the treatment disclosed herein in the treatment of diabetes reaches at least its blood glucose control treatment target, and the treatment target is maintained by discontinuation of treatment using insulin. In one embodiment, a patient using the treatment disclosed herein in the treatment of diabetes reaches at least its blood glucose control treatment target, and the treatment target is maintained by discontinuation of treatment using all other diabetes medications. In one embodiment, the patient blood glucose target is normal blood glucose or an HbA1c less than about 5.9% HbA1c. In one embodiment, the patient blood glucose target is normal blood glucose or an HbA1c less than about 5.7% HbA1c.

[0028] "Blood glucose control" refers to maintaining or reducing the target HbA1c level. "Improving" blood glucose control means reducing HbA1c, and "requiring further" blood glucose control means the need to reduce HbA1c. In one embodiment, "requiring further blood glucose control" means that the patient has not achieved the HbA1c target determined by the patient's physician.

[0029] As used herein, “HbA1c” refers to the level of glycated hemoglobin, which occurs when hemoglobin binds to 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 relation to 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 experience of side effects is improved compared to the average treatment experience using an FDA-approved tirzepatide dosing regimen.

[0030] As used herein, “first-line treatment” means initial and primary medical treatment for a condition. To avoid misunderstanding, first-line treatment of tilzepatide for type 2 diabetes means that the patient is not given metformin as first-line treatment for diabetes.

[0031] As used herein, “patient” or “multiple patients” refers to mammals requiring treatment for a condition or disorder. In one embodiment, the patient is a human being with a disease or condition who is unable to achieve their treatment goals. In one embodiment, the patient is susceptible to type 2 diabetes.

[0032] As used herein, “diabetes treatment goal” refers to the desired HbA1c level and / or weight loss determined by a healthcare professional. As used herein, “HbA1c goal” refers to the HbA1c level to be achieved, determined by the patient’s physician. Treatment goals may vary from patient to patient based on the physician’s assessment.

[0033] As used herein, "a treatment lasting at least 26 weeks" or "at least 52 weeks" means that the treatment may continue as long as the patient requires such treatment. Such treatment may be a chronic treatment that the patient continues for life, or the treatment may be interrupted intermittently after the specified period.

[0034] Example 1 Clinical reduction of basal insulin Eligible patients switched their diabetes treatment to standardized insulin glargine (100 IU / mL) therapy and discontinued glucose-lowering medications other than metformin up to 10 weeks prior to randomization. At the end of basal insulin stabilization, patients with glycated hemoglobin levels of 7.5% or higher were randomized (1:1:1:3) to receive subcutaneous injections of either once-weekly tirzepatide (5 mg, 10 mg, or 15 mg) or three times daily mealtime insulin lispro (100 IU / mL) for 52 weeks, followed by a 4-week safety follow-up period. Stratification was based on country, pre-randomization glycated hemoglobin level (≤8.5% or >8.5%), and baseline metformin use (yes or no).

[0035] Chilzepatide was initiated at 2.5 mg once weekly, and the dose was increased by 2.5 mg every four weeks until the randomization dose was reached, and this dose was maintained for the duration of the study.

[0036] Insulin lispro was initiated at 4 IU before each of the three largest meals daily. The dose was adjusted twice a week until week 24, and at least once a week thereafter, according to a standardized escalation algorithm, to achieve pre-lunch, pre-dinner, and bedtime blood glucose targets of 100–125 mg / dL.

[0037] At randomization, patients received a 30% reduction in their insulin glargine dose to lower their risk of hypoglycemia at the start of the study treatment. The dose was escalated weekly to a pre-breakfast glucose target of 100–125 mg / dL. Patients treated with tilzepatide were restricted from any escalation of insulin glargine for 4 weeks after randomization.

[0038] The results from the study show that tilzepatide in individual and pooled doses was statistically superior and clinically significant in reducing mean glycated hemoglobin levels (-1.92% to -2.3% vs. -1.1%) compared to basal bolus insulin therapy, and in achieving glycemic targets in individuals with long-term type 2 diabetes that is poorly controlled with basal insulin. These data demonstrate that patients treated with tilzepatide (5 mg, 10 mg, 15 mg) were able to reduce their basal insulin use from a median of 46 IU / day to 13 IU / day. This is comparable to the increase in basal insulin requirements in the insulin lispro group, which increased from a median of 46 IU / day to 62 IU basal insulin / day.

[0039] Tilzepatide treatment was associated with up to an 80% reduction in basal insulin requirements (15 mg tilzepatide), complete discontinuation of basal insulin use in up to 19% of patients (15 mg tilzepatide), and a 10-fold lower rate of clinically significant hypoglycemia compared to basal bolus insulin therapy.

[0040] In contrast, the addition of mealtime insulin resulted in a significant increase in daily insulin use of 112 IU in patients receiving basal bolus insulin.

[0041] Example 2 Tirzepatide (TZP) is a once-weekly GIP / GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). In phase 3 trials of SURPASS-1 (S-1) (monotherapy) and SURPASS-2 (S-2) (metformin), TZP substantially reduced HbA1c and body weight (BW) in people with T2D.

[0042] An exploratory post-hoc analysis examined the predictive value of HOMA2-B (C-peptide) from lower quartiles (lower beta-cell function or insulin resistance) [Q1] to higher quartiles [Q4] for achieving HbA1c (<39 mmol / mol, ≤48 mmol / mol) (<5.7%, ≤6.5%) in patients adhering to TZP treatment at week 40. The odds ratio (OR) was calculated from a logistic regression model using the overall mean as a reference.

[0043] The results showed that, with the exception of S-2 (using metformin), where subjects with Q1 HOMA2-B (lowest beta cell function) were remarkably unlikely to have HbA1c ≤ 48 mmol / mol (≤ 6.5%), TZP was equally likely to achieve BW and HbA1c targets in S-1 and S-2, regardless of baseline HOMA2-B and -IR quartiles.

[0044] Baseline HOMA2-B may predict patients who could benefit from tilzepatide monotherapy as a first-line medical treatment for glycemic control.

[0045] [Table 1]

[0046] Data presented as OR (95% CI). Values ​​in bold are statistically significant compared to the overall mean (p<0.05). Calculated from logistic regression models using the overall mean as reference. Abbreviations: CI = confidence interval, OR = odds ratio, adhere to TZP treatment = ≥75% treatment compliance, and receiving TZP treatment (5mg, 10mg, 15mg) at week 40 without salvage therapy, TZP = tilzepatide. Logistic regression included baseline values, pooled countries, TZP dose groups, and HOMA-B (C-peptide) quartiles. For S-1, prior use of oral hypoglycemic agents (yes / no) was also included.

[0047] Therefore, as this data shows, human subjects with HOMA2-B Q1 (low) status are more likely to reach treatment goals with TZP monotherapy compared to patients with HOMA2-B Q4 status, who are generally equally likely to reach treatment goals with TZP monotherapy or TZP metformin therapy.

[0048] array Sequence ID 1 Chilzepatid YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, and the 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 an epsilon-amino group, and the C-terminal amino acid is amidated as a C-terminal primary amide.

Claims

1. A method for improving blood glucose control in patients requiring improvement in blood glucose control, by administering tilzepatide or a pharmaceutically acceptable salt thereof, a) Determining the Homeostatic Model Assessment (HOMA) 2-B state of the patient, i. Obtaining or having obtained a biological sample from the aforementioned patient, ii. Performing or having performed HOMA 2-B evaluation on the sample, c) If the patient's HOMA 2-B is less than 1 (C-peptide), administer an effective dose of tilzepatide or a pharmaceutically acceptable salt thereof as first-line pharmaceutical treatment for type 2 diabetes, A method in which such treatment is administered for at least 26 weeks.

2. The method according to claim 1, wherein the treatment is administered for at least 52 weeks.

3. The method according to claim 1 or 2, wherein the patient has prediabetes.

4. The method according to any one of claims 1 to 3, wherein an effective amount of tilzepatide or a pharmaceutically acceptable salt thereof is administered once a week.

5. The method according to any one of claims 1 to 4, wherein the effective amount of tilzepatide is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg.

6. The method according to any one of claims 1 to 5, wherein the effective amount of tilzepatide is selected from the group consisting of 5 mg, 10 mg, and 15 mg.

7. The method according to any one of claims 1 to 6, wherein the tilzepatide or a pharmaceutically acceptable salt thereof is a monotherapy agent for treating blood glucose control.

8. A method for treating or preventing type 2 diabetes in a patient with low HOMA2-B (C-peptide), comprising administering a therapeutically effective dose of tilzepatide or a pharmaceutically acceptable salt thereof, wherein the tilzepatide or a pharmaceutically acceptable salt thereof is a first-line treatment for type 2 diabetes.

9. The method according to claim 8, wherein the treatment is continued for at least 26 weeks.

10. The method according to claim 8 or 9, wherein the treatment is continued for at least 52 weeks.

11. The method according to any one of claims 8 to 10, wherein the treatment excludes metformin.

12. The method according to any one of claims 8 to 11, wherein the patient has at least two risk factors selected from the group consisting of prediabetes, or excessive abdominal fat, obesity, sedentary lifestyle, family history, being over 45 years of age, gestational diabetes, and polycystic ovary syndrome.

13. The method according to any one of claims 8 to 12, wherein the patient has prediabetes.

14. The method according to any one of claims 8 to 13, wherein the HbA1c after 26 weeks of treatment is 6% or less.

15. A method for treating or preventing type 2 diabetes, A method comprising administering a therapeutically effective dose of tilzepatide or a pharmaceutically acceptable salt thereof to a human subject having low HOMA2-B, wherein the treatment is continued for at least 26 weeks.

16. The method according to claim 15, wherein the treatment is continued for at least 52 weeks.

17. The method according to claim 15 or 16, wherein the tilzepatide or a pharmaceutically acceptable salt thereof is administered as a first-line pharmacotherapy for type 2 diabetes.

18. The method according to any one of claims 15 to 17, wherein the treatment excludes the use of metformin.

19. The method according to any one of claims 15 to 18, wherein the treatment comprises tilzepatide or a pharmaceutically acceptable salt thereof as a monotherapy for type 2 diabetes.

20. The method according to any one of claims 15 to 19, wherein HOMA2-B is less than 1.

21. The method according to any one of claims 15 to 19, wherein HOMA2-B is in the lowest quartile of the standardized population.

22. A method for managing blood glucose control in a patient with long-term type 2 diabetes who uses basal insulin therapy to manage blood glucose control, comprising administering an effective dose of tilzepatide or a pharmaceutically acceptable salt thereof to such patient once weekly for at least 52 weeks.

23. The method according to claim 22, wherein the patient was diagnosed with type 2 diabetes more than 13 years prior to treatment with tilzepatide.

24. The method according to claim 22 or 23, wherein the basal insulin therapy is reduced during the treatment period.

25. The method according to any one of claims 22 to 24, wherein the basal insulin therapy is eliminated during the treatment period.

26. The method according to any one of claims 22 to 25, wherein the effective amount of tilzepatide is selected from the group consisting of 10 and 15 mg.

27. The method according to any one of claims 22 to 26, wherein 15 mg of tilzepatide is administered once a week.

28. The method according to any one of claims 22 to 27, wherein tilzepatide is administered subcutaneously.

29. The method according to any one of claims 22 to 28, wherein a patient whose blood glucose control is managed has an HbA1c of 7.0 or less.

30. The method according to any one of claims 22 to 29, wherein the treatment is continued for at least one calendar year.

31. The method according to any one of claims 22 to 29, wherein the treatment is continued for at least 18 months.

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