Telpotide for use in treatment of T2D

Abstract

The present invention provides methods for treating or preventing type 2 diabetes mellitus in patients with low HOMA2-B using tilpotide as a first-line diabetes mellitus drug treatment. The present invention provides methods of treating a patient suffering from long-term type 2 diabetes mellitus and reducing or eliminating basal insulin treatment with tilpotide, wherein such treatment lasts for at least 26 weeks.

Description

[0001] This invention relates to the field of medicine. More specifically, this invention provides a novel method for managing glycemic control in patients with long-term type 2 diabetes who require basal insulin therapy to control their blood glucose, the method comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to such patients once weekly for at least 52 weeks. On the other hand, it relates to the treatment or prevention of type 2 diabetes in patients with HOMA-2B less than 1, the method comprising administering a therapeutically effective amount of tirzepatide, wherein tirzepatide is a first-line treatment for type 2 diabetes.

[0002] This disclosure relates to methods of using telpolide for the prevention or treatment of type 2 diabetes, wherein the disease is characterized by impaired pancreatic β-cell function in a human individual (HOMA2-B first quartile, C-peptide). This disclosure also relates to administering telpolide to such patients to treat or prevent a disease characterized by impaired glycemic control. Certain aspects of this disclosure relate to the treatment or prevention of a disease in a human individual characterized by impaired glycemic control and impaired pancreatic β-cell function, wherein the human individual is selected based on the patient's HOMA2-B (C-peptide) status, and / or telpolide is used as a pharmaceutical monotherapy for type 2 diabetes. Diseases that can be treated or prevented using telpolide or the methods disclosed herein include, for example, type 2 diabetes and conditions in which glycemic control is beneficial. In some embodiments, this disclosure relates to maintaining pancreatic β-cell function in an individual, as indicated by HOMA2-B (C-peptide). In some embodiments, this disclosure relates to selecting patients for the restoration or improvement of pancreatic β-cell function in a human individual.

[0003] Diabetes is a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In type 2 diabetes (T2D), the combined effect of impaired insulin secretion and insulin resistance is associated with elevated blood glucose levels. For patients with long-term type 2 diabetes and uncontrolled hyperglycemia, insulin therapy remains the cornerstone and often the final treatment. Insulin therapy typically begins with basal insulin and is gradually titrated; however, as β-cell function gradually declines, many patients eventually require intensive prandial insulin therapy. The basal-bolus insulin regimen (i.e., once-daily basal insulin and three-meal-daily prandial insulin) has historically been considered the gold standard insulin therapy for patients with long-term type 2 diabetes who are poorly controlled by basal insulin therapy by most treatment guidelines; however, this type of therapy often requires increasing insulin doses and typically involves increasingly complex treatment plans. Such complex insulin therapy plans may be associated with an increased risk of hypoglycemia. Treatment plans that reduce the risks associated with basal insulin therapy for type 2 diabetes are needed. In one implementation plan, basal insulin therapy is associated with patients with long-term type 2 diabetes. Therefore, providing treatment options with acceptable benefit / risk characteristics remains an important medical need for patients with long-term type 2 diabetes whose type 2 diabetes cannot be controlled by basal insulin.

[0004] Therefore, implementation plans are provided to meet the needs of such treatments.

[0005] Methods of improving glycemic control in patients who need telpolide include:

[0006] a) Determine the patient's Homeostasis Model Assessment (HOMA) 2-B status, wherein the determination includes

[0007] i. Obtaining or having already obtained biological samples from the patient;

[0008] ii. The sample has been or is being evaluated using HOMA 2-B.

[0009] b) If the patient's HOMA 2-B is less than 1 (C-peptide), administer an effective dose of telpolide as first-line treatment for type 2 diabetes; and

[0010] This type of treatment is administered for at least 26 weeks.

[0011] Methods of improving glycemic control in patients who need telpolide include:

[0012] a) Determine the patient's Homeostasis Model Assessment (HOMA) 2-B status, wherein the determination includes

[0013] i. Obtaining or having already obtained biological samples from the patient;

[0014] ii. The sample has been or is being evaluated using HOMA 2-B.

[0015] b) If the patient's HOMA 2-B is less than 1 (C-peptide), administer an effective dose of telpolide as first-line treatment for type 2 diabetes; and

[0016] This type of treatment is administered for at least 52 weeks.

[0017] Methods for treating or preventing type 2 diabetes in patients with HOMA-2B less than 1 include administering a therapeutically effective amount of telpolide or a pharmaceutically acceptable salt thereof, wherein telpolide is a first-line drug treatment for type 2 diabetes.

[0018] Methods of treating or preventing type 2 diabetes in patients with HOMA-2B less than 1 include administering a therapeutically effective amount of telpolide or a pharmaceutically acceptable salt thereof, wherein telpolide is a first-line drug treatment for type 2 diabetes; and wherein such treatment is administered for at least 26 weeks.

[0019] This invention provides a treatment option for patients with long-term type 2 diabetes who cannot achieve their glycemic control goals using basal insulin. Furthermore, there is a need to provide treatment methods for patients with long-term type 2 diabetes that provide glycemic control without the use of insulin.

[0020] US9474780 generally describes compositions containing GIP and GLP-1 receptor agonists administered via a parenteral route, and generally discloses a wide dose range of up to about 30 mg per person per week. US9474780 discloses the use of GIP / GLP1 co-agonists for the treatment of diabetes, obesity, and other conditions. US9474780 describes and claims protection for telpolide. Telpolide has been approved by the U.S. Food and Drug Administration as an adjunct to diet and exercise for the treatment of type 2 diabetes.

[0021] In another aspect, the present invention provides the use of telpolide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving glycemic control in patients in need, wherein the patients are identified as having low HOMA-2B.

[0022] US 9,474,780 teaches that telpolide can be used to treat diabetes, where “treatment” includes inhibiting, slowing, stopping, or reversing the progression or severity of existing symptoms or impairments. Despite advances in diabetes treatment, many patients receiving such treatments fail to achieve their glycemic control or HbA1c targets. As used herein, the term “insulin” refers to basal or prandial insulin, recognized by those skilled in the art and approved by a regulatory agency. As used herein, “basal insulin” refers to long-acting insulin, such as insulin glargine. As used herein, “prandial insulin” refers to short-acting or ultra-rapid-onset insulin, such as insulin lispro. The term “insulin” is intended to encompass both basal and prandial insulin. As used herein, insulin is expected to be administered according to its respective FDA or similar regulatory agency-approved label dosage instructions.

[0023] In some embodiments, telpolide is administered for at least 26 weeks. In some embodiments, telpolide is administered for at least 52 weeks. In some embodiments, telpolide is administered for at least 6 months. In some embodiments, telpolide is administered for at least one year.

[0024] As used herein, “HOMA-2B” refers to the 2B c-peptide as assessed by a steady-state model. As used herein, “low HOMA-2B” means a value less than approximately 1. In one implementation, “low HOMA-2B” means that HOMA-2B is in the lowest quartile relative to the standard population.

[0025] As used herein, the terms "diabetes medication" or "diabetes drugs" refer to medications approved by the relevant regulatory agency for the treatment of glycemic control or type 2 diabetes. As used herein, "first-line treatment medication" refers to initial medications for the treatment of type 2 diabetes, such as those approved by the relevant regulatory agency for the treatment of glycemic control or type 2 diabetes.

[0026] In one implementation, telpolide or a pharmaceutically acceptable salt thereof is administered to patients with low HOMA-2B as a first-line treatment for glycemic control or type 2 diabetes.

[0027] In one implementation, patients maintain their target HbA1c level for at least one month without further insulin administration.

[0028] As used herein, “predisposition to type 2 diabetes” refers to the presence of at least two known risk factors for type 2 diabetes, such as excess abdominal fat, obesity, a sedentary lifestyle, family history, age over 45, gestational diabetes, or polycystic ovary syndrome. In one implementation plan, “predisposition to type 2 diabetes” refers to a diagnosis of prediabetes. The typical HbA1c range for prediabetes is approximately 5.7% to approximately 6.4%.

[0029] The dosage of the telpolide of the present invention may have the following specific concentrations: 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 present in pre-filled syringes. Such pre-filled syringes can be used to administer half a milliliter of such composition to each patient per dose. The dosage of the present invention is typically administered subcutaneously. The dosage is typically administered using a pre-filled disposable pen, a reusable pen, or an automated pen-type syringe. In one embodiment, the device is the automated injection device claimed in U.S. Patent 8,734,394.

[0030] As used herein, “telpoeptide” refers to the GIP / GLP1 dual agonist peptide as described in US 9,474,780 and as described in CAS Registry No. 2023788-19-2.

[0031] The telpolide described in Example 1 of US 9,474,780 has the following sequence: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0032] Where X1 is Aib; X2 is Aib; K at position 20 is represented by (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H is chemically modified by coupling with the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to form a C-terminal primary amide (SEQ ID NO:1).

[0033] As used herein, the term "application" means administration by a nurse, healthcare provider, patient, or any other individual, including self-application. As used herein, application may include prescribing, dispensing, or any form of delivery assisted by a healthcare professional.

[0034] As used herein, "pharmaceutically acceptable salt" is well known to those skilled in the art. In one embodiment, the pharmaceutically acceptable salt is telpolide trifluoroacetate. In one embodiment, telpolide is administered in a non-salt form.

[0035] As used herein, the term "biomarker" refers to a laboratory measurement that reflects disease process activity. Biomarkers can be used to diagnose diseases or symptoms and are typically quantitatively correlated (positively or negatively) with disease progression. In a clinical trial setting, a biomarker is a measure of the effectiveness of a specific treatment and may be correlated with, but not necessarily with, the actual clinical endpoint; that is, a biomarker is a surrogate measure of the clinical endpoint.

[0036] As used herein, the term "treatment," etc., refers to actions that slow or reduce the progression of a disease or disorder. This term includes alleviating, improving, or reducing one or more symptoms of the disorder or condition, even if the disorder or condition is not eliminated or its progression is not slowed. As used herein, HbA1c targets are the HbA1c biomarker levels that a patient wishes to achieve, determined by a physician through assessment of the patient's condition, age, comorbidities, etc.

[0037] As used in this article, "long-term type 2 diabetes" refers to a patient diagnosed with type 2 diabetes for at least 13 years. This term may also refer to patients on basal insulin therapy who are unable to achieve their blood glucose or HbA1c targets.

[0038] In one embodiment, a patient treating diabetes using the methods disclosed herein achieves at least their glycemic control target and maintains that target upon discontinuation of insulin therapy. In another embodiment, a patient treating diabetes using the methods disclosed herein achieves at least their glycemic control target and maintains that target upon discontinuation of all other diabetes medications. In one embodiment, the patient's glycemic target is normal blood glucose or HbA1c below approximately 5.9% HbA1c. In yet another embodiment, the patient's glycemic target is normal blood glucose or HbA1c below approximately 5.7% HbA1c.

[0039] "Glycemic control" refers to maintaining or lowering an individual's HbA1c level; "improved" glycemic control refers to lowering HbA1c; "requiring further" glycemic control refers to the need to lower HbA1c. In one implementation plan, "requiring further glycemic control" means that the patient has not yet achieved the HbA1c target set by their physician.

[0040] As used herein, "HbA1c" refers to glycated hemoglobin level, which is produced when hemoglobin binds to glucose in the blood. HbA1c level is a commonly used measure of glycemic control in patients with diabetes, and a decrease in HbA1c level generally indicates improved glycemic control. In the context of the method of the present invention, the method of the present invention results in a decrease in HbA1c. In some embodiments, HbA1c is reduced relative to the expected HbA1c level when treated with an FDA-approved telpolide dosing regimen. In some embodiments, patients experience improved side effects relative to the average treatment experience with an FDA-approved telpolide dosing regimen.

[0041] As used in this article, "first-line treatment" refers to initial and primary drug treatment for this condition. For the avoidance of doubt, telpolide is used as first-line treatment for type 2 diabetes when the patient is not receiving metformin as a first-line diabetes medication.

[0042] As used herein, "patient" or "multiple patients" refers to a mammal requiring treatment for a condition or disorder. In one implementation, a patient is a person suffering from a disease or disorder in which the patient is unable to achieve their treatment goals. In one implementation, a patient is predisposed to type 2 diabetes.

[0043] As used herein, a “diabetes treatment goal” is a desired HbA1c level and / or weight loss determined by a healthcare professional. As used herein, an 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.

[0044] As used in this article, "at least 26 weeks" or "at least 52 weeks" means that treatment can continue as long as the patient requires it. This treatment can be a long-term treatment that continues for the patient's entire life, or it can be intermittently paused after the aforementioned time period.

[0045] Example 1

[0046] Clinically lowering basal insulin

[0047] Eligible patients switched their diabetes treatment regimen to standardized insulin glargine (100 IU / mL) and discontinued all glucose-lowering medications except metformin within 10 weeks prior to randomization. After basal insulin stabilization, patients with HbA1c levels of 7.5% or higher were randomized in a 1:1:1:3 ratio to receive either once-weekly subcutaneous telpoxetine (5 mg, 10 mg, or 15 mg) or three-times daily lispro insulin (100 IU / mL) for 52 weeks, followed by a 4-week safety follow-up. Stratification was based on country, pre-randomization HbA1c level (≤8.5% or >8.5%), and baseline metformin use (yes or no).

[0048] The dose of telpolide was started at 2.5 mg once a week, increased by 2.5 mg every 4 weeks until a randomly assigned dose was reached and maintained during the study period.

[0049] Lispro insulin was started at 4 IU, three times daily before main meals. The dose was adjusted twice weekly according to the standardized titration algorithm until week 24, and then at least once weekly thereafter, to achieve a target blood glucose level of 100 to 125 mg / dL before lunch, dinner, and bedtime.

[0050] Upon randomization, patients will have their insulin glargine dose reduced by 30% to minimize the risk of hypoglycemia upon initiation of study treatment. Dosage will be titrated weekly to achieve a pre-breakfast blood glucose target of 100 to 125 mg / dL. Patients receiving telpopritide should not have any insulin glargine dose escalation within 4 weeks of randomization.

[0051] The results showed that both single-dose and combined-dose telpotetide, compared with basal-prandial insulin therapy, had statistically significant advantages and clinical significance in reducing mean glycated hemoglobin levels (-1.92% to -2.3% vs -1.1%) and in achieving glycemic targets in patients with long-term type 2 diabetes and poor control with basal insulin. These data indicate that patients treated with telpotetide (5 mg, 10 mg, 15 mg) were able to reduce their median basal insulin requirement from 46 IU / day to 13 IU / day. In contrast, the basal insulin requirement increased in the lispro insulin group, with the median basal insulin requirement increasing from 46 IU / day to 62 IU / day.

[0052] Treatment with telposide is associated with the following: up to 80% reduction in basal insulin requirements (15 mg telposide), up to 19% of patients completely discontinuing basal insulin use (15 mg telposide), and a 10-fold reduction in the incidence of clinically significant hypoglycemia compared to basal-meal insulin therapy.

[0053] Conversely, with the addition of mealtime insulin, the daily insulin dose of patients on basal-meal insulin therapy increased significantly by 112 IU.

[0054] Example 2

[0055] Telposide (TZP) is a once-weekly GIP / GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). In the Phase 3 clinical trials of SURPASS-1 (S-1) (monotherapy) and SURPASS-2 (S-2) (metformin therapy), TZP significantly reduced HbA1c and body weight (BW) in patients with T2D.

[0056] Exploratory post-hoc analyses examined the predictive value of HOMA2-B (C-peptide) by achieving HbA1c (<39 mmol / mol, ≤48 mmol / mol) (<5.7%, ≤6.5%) in patients who adhered to TZP treatment at week 40, from low quartile (low β-cell function or insulin resistance) [Q1] to high quartile [Q4]. Odds ratios (ORs) were calculated using a logistic regression model with the overall mean as a reference.

[0057] The results showed that regardless of baseline HOMA2-B and -IR quartiles, TZP had the same probability of achieving BW and HbA1c targets in S-1 and S-2, except in S-2 (using metformin), where individuals with Q1 HOMA2-B (lowest β-cell function) were significantly less likely to have HbA1c ≤48 mmol / mol (≤6.5%).

[0058] Baseline HOMA2-B can predict patients who may benefit from telpoxetine monotherapy as a first-line treatment for glycemic control.

[0059] Table 1.

[0060]

[0061] Data are presented as odds ratios (95% CI). Bold values ​​are statistically significant compared to the population mean (p < 0.05). Logistic regression models were used with the population mean as a reference. Abbreviations: CI = confidence interval; OR = odds ratio; adherence to TZP treatment = treatment adherence ≥ 75% at week 40 and currently receiving TZP (5 mg, 10 mg, 15 mg) without rescue therapy; TZP = telpolide. Logistic regression included baseline values, pooled country, TZP dose group, and HOMA-B (C-peptide) quartiles. For S-1, prior use of oral hypoglycemic agents was also included (yes / no).

[0062] Therefore, this data shows that individuals with a low HOMA2-B Q1 status are more likely to achieve their treatment goals with TZP monotherapy compared to patients with a low HOMA2-B Q4 status, while patients with a low HOMA2-BQ4 status are also likely to achieve their treatment goals with either TZP monotherapy or TZP metformin treatment.

[0063] sequence

[0064] SEQ ID NO:1

[0065] Telpoeptide

[0066] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0067] Where X1 is Aib; X2 is Aib; K at position 20 is represented by (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H is chemically modified by coupling with the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

Claims

1. Methods of administering telpolide or its pharmaceutically acceptable salts to improve glycemic control in patients in need, including a) Determine the patient's Homeostasis Model Assessment (HOMA) 2-B status, wherein the determination includes i. Obtaining or having already obtained biological samples from the patient; ii. The sample has been or has already undergone HOMA 2-B evaluation; b) If the patient's HOMA 2-B is less than 1 (C-peptide), administer an effective amount of telpolide or a pharmaceutically acceptable salt thereof as first-line treatment for type 2 diabetes; and This type of treatment is administered for at least 26 weeks.

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

3. The method claimed in claim 1 or claim 2, wherein the patient has prediabetes.

4. The method claimed in any one of claims 1 to 3, wherein the effective amount of telpolide or a pharmaceutically acceptable salt thereof is administered once weekly.

5. The method claimed in any one of claims 1 to 4, wherein the effective amount of said telpolide is selected from 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg.

6. The method claimed in any one of claims 1 to 5, wherein the effective amount of said telpolide is selected from 5 mg, 10 mg and 15 mg.

7. The method claimed in any one of claims 1 to 6, wherein telpolide or a pharmaceutically acceptable salt thereof is a monotherapy drug for treating glycemic control.

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

9. The method claimed in claim 8, wherein the treatment lasts for at least 26 weeks.

10. The method claimed in any one of claims 8 and 9, wherein the treatment lasts for at least 52 weeks.

11. The method claimed in any one of claims 8 to 10, wherein the treatment does not include metformin.

12. The method claimed in any one of claims 8 to 11, wherein the patient has prediabetes or has at least two risk factors selected from the following: excess abdominal fat, obesity, sedentary lifestyle, family history, age over 45, gestational diabetes, and polycystic ovary syndrome.

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

14. The method claimed in any one of claims 8 to 13, wherein HbA1c is 6% or lower after 26 weeks of treatment.

15. A method of treating or preventing type 2 diabetes, comprising administering a therapeutically effective amount of telpolide or a pharmaceutically acceptable salt thereof to a human individual having low HOMA 2-B, wherein said treatment lasts for at least 26 weeks.

16. The method claimed in claim 15, wherein the treatment lasts for at least 52 weeks.

17. The method claimed in any one of claims 15 to 16, wherein telpolide or a pharmaceutically acceptable salt thereof is administered as a first-line drug treatment for type 2 diabetes.

18. The method claimed in any one of claims 15 to 17, wherein the treatment does not include the use of metformin.

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

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

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

22. A method for managing glycemic control in patients with long-term type 2 diabetes and who are managed with basal insulin therapy, comprising administering an effective amount of telpolide or a pharmaceutically acceptable salt thereof to such patients once weekly for at least 52 weeks.

23. The method claimed in claim 22, wherein the patient has been diagnosed with type 2 diabetes for more than 13 years prior to treatment with telpotrioside.

24. The method claimed in any one of claims 22 to 23, wherein the basal insulin treatment is reduced during the treatment.

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

26. The method claimed in any one of claims 22 to 25, wherein the effective amount of telpolide is selected from 10 and 15 mg.

27. The method claimed in any one of claims 22 to 26, wherein 15 mg of telpolide is administered once weekly.

28. The method claimed in any one of claims 22 to 27, wherein telpolide is administered subcutaneously.

29. The method claimed in any one of claims 22 to 28, wherein the patient managing glycemic control has an HbA1c of 7.0 or lower.

30. The method claimed in any one of claims 22 to 29, wherein the treatment lasts for one calendar year.

31. The method claimed in any one of claims 22 to 29, wherein the treatment lasts for at least 18 months.

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