EP4687948A1

EP4687948A1 - Tirzepatide for use in treating t2d

Info

Publication number: EP4687948A1
Application number: EP24721356.4A
Authority: EP
Inventors: Laura FERNANDEZ LANDO; Hirenkumar Patel; Melissa Kay Thomas
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2023-03-31
Filing date: 2024-03-28
Publication date: 2026-02-11
Also published as: WO2024206552A1; MX2025011528A; CN121001735A; KR20250163978A; JP2026513204A

Abstract

The present invention provides a method for treating or preventing type 2 diabetes in a patient the patient has low HOMA2-B, using tirzepatide as the first line pharmaceutical diabetes treatment. Provided is a method for treating a patient with long-standing type 2 diabetes using tirzepatide and decreased or eliminated basal insulin treatment, wherein such treatment continues for at least 26 weeks.

Description

TIRZEPATIDE FOR USE IN TREATING T2D

The present invention relates to the field of medicine. More particularly, the present invention provides a new method for managing glycemic control in a patient with long-standing type 2 diabetes requiring basal insulin treatment to manage glycemic control, comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once weekly to such patient for at least 52 weeks. Another aspect relates to treating or preventing type 2 diabetes in a patient with H0MA-2B less than 1 , comprising administering a therapeutically effective amount of tirzepatide, wherein tirzepatide is the first line type 2 diabetes treatment.

The present disclosure is related to methods of preventing or treating type 2 diabetes using tirzepatide, wherein the disease is characterized by poor pancreatic beta cell function (H0MA2-B Quartile 1, c-peptide) in a human subject. The present disclosure is also related to administration of tirzepatide to such patient for treating or preventing a disease characterized by impaired glycemic control. Some aspects of the present disclosure are related to treating or preventing a disease characterized by impaired glycemic control with poor pancreatic beta cell function in human subjects, wherein the human subjects are selected, and/or treated with tirzepatide as a pharmaceutical monotherapy for type 2 diabetes, based on the patient’s HOMA 2-B (C-peptide) status. The diseases that can be treated or prevented using tirzepatide, or methods disclosed herein include, e.g., type 2 diabetes, and a condition wherein glycemic control is beneficial. In some embodiments, the present disclosure is related to preserving pancreatic beta cell function in the subject, as shown by HOMA 2-B (C-peptide). In some embodiments, the present disclosure is related to selecting a patient for restoring or improving pancreatic beta cell function of the human subject.

Diabetes mellitus is a chronic disorder characterized by hyperglycemia resulting from 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. Insulin therapy remains a cornerstone and often the last resource for patients with long-standing type 2 diabetes and uncontrolled hyperglycemia. Insulin is generally initiated with basal insulin and titrated gradually; however, with progressive loss of beta-cell function, many patients eventually require intensification of therapy using prandial insulin. A basal-bolus insulin regimen (i.e., once daily basal insulin and thrice-daily prandial insulin), has historically been considered the gold- standard insulin regimen by most treatment guidelines for patients with long-standing type 2 diabetes poorly controlled with basal insulin; however, such treatment often involves a need to increase the insulin dose and often involves increasingly complex treatment plans. Such complex insulin treatment plans may be associated with increased risk of hypoglycemia. There is a need for a treatment plan to mitigate the risks associated with basal insulin treatment of type 2 diabetes. In an embodiment, the basal insulin treatment is associated with a patient with long-standing type 2 diabetes. Therefore, there remains an important medical need to provide a treatment option with an acceptable benefit/risk profde for a patient with long-standing type 2 diabetes and unable to control their type 2 diabetes using basal insulin.

Accordingly, provided are embodiments to address the need for such treatments. A method of administering tirzepatide to improve glycemic control in a patient in need thereof, comprising a) Determine homeostatic model assessment (HOMA) 2-B status of the patient wherein the determination comprises i. Obtaining or having obtained a biological sample from the patient; ii. performing or having performed a HOMA 2-B assessment on the sample; b) If the patient’s HOMA 2-B is less than one (C-Peptide) then administer an effective amount of tirzepatide as a first line type 2 diabetes pharmaceutical treatment; and

Wherein such treatment are administered at least 26 weeks.

A method of administering tirzepatide to improve glycemic control in a patient in need thereof, comprising a) Determine homeostatic model assessment (HOMA) 2-B status of the patient wherein the determination comprises i. Obtaining or having obtained a biological sample from the patient; ii. performing or having performed a HOMA 2-B assessment on the sample; b) If the patient’s HOMA 2-B is less than one (C-Peptide) then administer an effective amount of tirzepatide as a first line type 2 diabetes pharmaceutical treatment; and

Wherein such treatment are administered at least 52 weeks.

A method for treating or preventing type 2 diabetes in a patient with HOMA- 28 less than 1 , comprising administering a therapeutically effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein tirzepatide is the first line type 2 diabetes pharmaceutical treatment.

A method for treating or preventing type 2 diabetes in a patient with HOMA- 28 less than 1 , comprising of administering a therapeutically effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein tirzepatide is the first line type 2 diabetes pharmaceutical treatment; and wherein such treatment is administered at least 26 weeks.

The present invention provides a treatment option for such long-standing type 2 diabetes patients unable to achieve their glycemic control goals using basal insulin. Further there is a need for a treatment to provide glycemic control treatment for a patient with long-standing type 2 diabetes, wherein the treatment provides glycemic control without the use of insulin.

US9474780 generally describes compositions containing a GIP and GLP-1 receptor agonist administered by parenteral routes, and generally discloses a wide dosage range up to about 30 mg per person per week. US9474780 discloses the use of GIP/GLP1 co-agonists for treating diabetes, obesity, and other conditions. US9474780 describes and claims tirzepatide. Tirzepatide is approved by the U.S. Food and Drug Agency for use in treating type 2 diabetes, as an adjunct to diet and exercise.

In another aspect, the present invention provides a 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 said patient is determined to have low HOMA-2B.

US 9,474,780 teaches that tirzepatide is useful for the treatment of diabetes, wherein “treating” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. Despite advances in the treatment of diabetes, many patients receiving such treaement are unable to reach their glycemic control goal or HbAlc goal. As used herein, the term “insulin” means a basal insulin or prandial insulin, as recognized by the skilled artisan and approved by regulatory agencies. As used herein “basal insulin” means an insulin that is longer acting, for example, insulin glargine and the like. As used herein “prandial insulin” means shorter acting insulin or ultrarapid acting insulin, for example insulin lispro. The term “insulin” is intended to embrace both basal insulin and prandial insulin. As used herein, it is contemplated that a insulin will be administered in accordance with its respective FDA, or similar regulatory agency, approved label dosing instructions.

In certain embodiments, tirzepatide is administered for at least 26 weeks. In certain embodiments, tirzepatide is administered for at least 52 weeks. In certain embodiments, tirzepatide is administered for at least 6 months. In certain embodiments, tirzepatide is administered for at least one year.

As used herein “H0MA-2B” means homeostasis model assessment 2B c-petide. As used herein “low H0MA-2B” means a value less than about 1. In an embodiment, “low H0MA-2B” means relative to a standard population, the H0MA-2B is in the lowest quartile.

As used herein, the term “diabetes medication,” “diabetes medicine” and the like, means a medication approved by the pertinent regulatory agency for use in the treatment of glycemic control or Type II diabetes. As used herein “first line treatment” means initial medication for use in treatment of type 2 diabetes, as approved by the pertinent regulatory agency for use in the treatment of glycemic control or Type II diabetes.

In an embodiment, a patient with low H0MA-2B is administered tirzepatide, or a pharmaceutically acceptable salt thereof, as first line treatment for glycemic control or type 2 diabetes.

In an embodiment, the patient maintains their HbAlc goal level for at least one month without further insulin administration.

As used herein “susceptible to type 2 diabetes” means the patient has as least 2 known risk factors for type 2 diabetes, for example, excess abdominal fat, obesity, sedentary lifestyle, family history, over the age of 45, gestational diabetes, polycystic ovary syndrome. In an embodiment “susceptible to type 2 diabetes” means the patient is diagnosed with prediabetes. Typical HbAlc ranges for prediabetes are between about 5.7% to about 6.4%. The tirzepatide doses of 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 presented in a pre-filled syringe. Such pre-filled syringe may be useful for administering one half milliliter of such composition per patient per dose. The doses of the present invention are typically administered subcutaneously. The doses are typically administered using a pre-filled, disposable pen, reusable pen, or automatic pen injector. In an embodiment, the device is an automatic injection apparatus as claimed by U.S. Patent 8,734,394.

As used herein, “tirzepatide” means a GIP/GLP1 dual agonist peptide as described in US 9,474,780 and described by CAS Registry Number: 2023788-19-2.

Tirzepatide is described in Example 1 of US 9,474,780, with the following sequence: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS wherein Xi is Aib; X2 is Aib; 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-(YGlu)i-CO-(CH2)i8-CO2H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).

As used herein, the term “administering” means the administration by a nurse, health care provider, patient or any other individual including self-administration. As used herein, administration may include prescribing, dispensing, or assisting in any way with delivery, as conducted by a health care professional.

As used herein, “pharmaceutically acceptable salt” is well known to the skilled artisan. In an embodiment is a pharmaceutically acceptable salt that is a tirzepatide trifluoroacetate salt. In an embodiment is tirzepatide is administered as a non-salt.

As used herein, the term “biomarker”, means a laboratory measurement that reflects the activity of a disease process. Biomarkers may be used to diagnose a disease or condition, and usually quantitatively correlate (either directly or inversely) with disease progression. In the clinical trial setting, a biomarker is a measure of the effect of a specific treatment that may correlate with an actual clinical endpoint but does not necessarily have a precise relationship; that is, a biomarker is a substitute measure for a clinical endpoint.

As used herein, the terms “treatment,” “treat,” “treating,” and the like, mean to include slowing or attenuating the progression of a disease or disorder. The terms include to alleviate, ameliorate, or reduce one or more symptoms of a disorder or condition, even if the disorder or condition is not eliminated or if the progression is not slowed. As used herein, HbAlc goal is an HbAlc biomarker level to be achieved by the patient, determined by a physician by assessing patient status, age, comorbidities and the like.

As used herein “long-standing type 2 diabetes” means that a patient, diagnosed with type 2 diabetes for at least 13 years. The term may mean a patient using basal insulin is unable to achieve their glycemic or HbAlc goal.

In an embodiment, a patient using a treatment disclosed herein in the treatment of diabetes reaches at least their glycemic control treatment goal, and the treatment goal is maintained with cessation of treatment using insulin. In an embodiment, a patient using a treatment disclosed herein in the treatment of diabetes reaches at least their glycemic control treatment goal, and the treatment goal is maintained with cessation of treatment using all other diabetes medication. In an embodiment, the patient glycemic goal is normoglycemia, or HbAlc less than about 5.9% HbAlc. In an embodiment, the patient glycemic goal is normoglycemia, or HbAlc less than about 5.7% HbAlc.

“Glycemic control” refers to the maintenance or reduction of a subject’s HbAlc levels; “improving]” glycemic control refers to reductions in HbAlc; and “in need of further” glycemic control refers to a need for reductions in HbAlc. In an embodiment “in need of further glycemic control” means that the patient has not achieved their HbAlc goal determined by their physician.

As used herein “HbAlc” refers to glycated hemoglobin levels, which develop when hemoglobin joins with glucose in the blood. HbAlc levels are a commonly used measure of glycemic control in patients with diabetes, with decreased HbAlc levels generally indicating improved glycemic control. In the context of the methods of the present invention, the methods of the present invention result in a decrease in HbAlc. In certain embodiments, the HbAlc is decreased relative to the HbAlc levels expected from treatment using the FDA approved tirzepatide dosing regimen. In certain embodiments, the patient side effect experience is improved relative to average treatment experience using FDA approved tirzepatide dosing regimen.

As used herein “first line treatment” means initial pharmaceutical treatment and primary pharmaceutical treatment for the condition. For avoidance of doubt, tirzepatide first line treatment for type 2 diabetes means that the patient is not administered metformin as the first line diabetes treatment.

As used herein “patient” or “patients” refers to a mammal in need of treatment for a condition or disorder. In an embodiment, the patient is a human with a disease or condition wherein the patient is unable to achieve their treatment goal. In an embodiment, a patient is susceptible to type 2 diabetes

As used herein “diabetes treatment goal” is the desired HbAlc level and/or weight loss determined by a health care professional. As used herein, HbAlc goal means an HbAlc level to achieve as determined by said patient’s physician. A treatment goal may vary from patient to patient based on physician assessment.

As used herein treatment continues for at “at least 26 weeks” or “at least 52 weeks” means that the treatment may continue for so long as the patient requires such treatment. Such treatment may be chronic treatment that the patient will continue for their lifetime, or treatment may be intermittently paused after the stated time period.

Example 1

Clinical Reduction in Basal Insulin

Eligible patients switched their diabetes treatment to a standardized therapy of insulin glargine (100 IU per mL) and discontinued glucose-lowering medications except for metformin up to 10 weeks before randomization. At the end of basal insulin stabilization, patients with glycated hemoglobin level 7.5% or greater were randomized (1: 1:1:3) to receive subcutaneous injection of once weekly tirzepatide (5 mg, 10 mg, or 15 mg) or thrice-daily prandial insulin lispro (100 IU per 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).

Tirzepatide was initiated at 2.5 mg once weekly and increased by 2.5 mg every 4 weeks until the randomized dose was achieved and maintained for the study duration. Insulin lispro was initiated at 4 IU prior to the three largest meals of the day. Doses were adjusted twice weekly until Week 24 and at least once weekly after Week 24 to achieve a pre-lunch, pre-dinner and bedtime blood glucose target of 100 to 125 mg/dL following a standardized titration algorithm.

At randomization, patients reduced insulin glargine doses by 30% to lower hypoglycemia risk due to study treatment initiation. Doses were titrated weekly to a prebreakfast blood glucose target of 100 to 125 mg/dL. Tirzepatide -treated patients were restricted from any up-titration of insulin glargine for 4 weeks after randomization.

Results from the study show that tirzepatide, at individual and pooled doses, was statistically superior and clinically meaningful in reducing mean glycated hemoglobin level compared to basal-bolus insulin therapy (-1.92% to -2.3% versus -1.1%) and in achieving glycemic targets in people with long-standing type 2 diabetes poorly controlled with basal insulin. These data demonstrate that patients treated with tirzepatide (5 mg, lOmg, 15mg) were able to decrease their basal insulin use from a median of 46 lU/day to 13 lU/day. This compares with increased basal insulin requirement for the insulin lispro group, wherein the median increased form 46 lU/day to 62 IU basal insulin per day.

Tirzepatide treatment was associated with up to 80% reduction in basal insulin requirement (15mg tirzepatide), up to 19% of patients completely discontinuing basal insulin use (15 mg tirzepatide), and a 10-fold lower rate of clinically significant hypoglycemia versus basal-bolus insulin therapy.

In contrast, with addition of prandial insulin patients in basal-bolus had significant increase in daily insulin use of 112 IU.

Example 2

Tirzepatide (TZP) is a once-weekly GIP/GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). In the SURPASS- 1 (S-l) (monotherapy) and SURP ASS-2 (S-2) (on metformin) Phase 3 trials, TZP substantially reduced HbAlc and body weight (BW) in people with T2D. Exploratory post hoc analyses examined the predictive value of H0MA2-B (C -peptide) by quartiles low (lower beta-cell function or insulin resistance) [QI] to high [Q4] for achieving HbAlc (<39 mmol/mol, <48 mmol/mol) (<5.7%, <6.5%) for those adherent to TZP treatment at Week 40. Odds ratios (OR) were calculated from logistic regression models using the overall mean as the reference.

The results showed that TZP was equally likely to achieve BW and HbAlc targets in S-l and S-2 regardless of baseline HOMA2-B and -IR quartiles, with the exception of S-2 (with metformin) where subjects with QI HOMA2-B (lowest beta-cell function) were significantly less likely HbAlc <48 mmol/mol (<6.5%).

Baseline HOMA2-B, may predict patients that may benefit from tirzepatide monotherapy as first line pharmaceutical treatment for glycemic control. Table 1.

Data presented as OR (95% CI). Values in bold are significant (p<0.05) vs overall mean. Calculated from logistic regression models using the overall mean as the reference. Abbreviations: CI = confidence interval; OR = odds ratio; Adherent to TZP Treatment = >75% treatment compliance and on TZP treatment (5mg, lOmg, 15mg) at week 40 without rescue therapy; TZP = tirzepatide.

The logistic regression included baseline value, pooled country, TZP dose group, HOMA-B (C- peptide) quartiles. For S-l, the prior use of oral antihyperglycemic medication (yes/no) was also included.

Thus, as can be seen from this data, a human subject with HOMA2-B QI (low) status is more likely to reach treatment goals with TZP monotherapy compared with a patient having HOMA2-B Q4 status who is generally equally likely to reach a treatment goal with TZP monotherapy or with TZP Metformin treatment.

Sequences

SEQ ID NO:1

Tirzepatide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS wherein Xi is Aib; X2 is Aib; 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-(yGlu)i-CO-(CH2)i8-CO2H; and the C-terminal amino acid is amidated as a C-terminal primary amide

Claims

WE CLAIM:

1. A method of administering tirzepatide, or a pharmaceutically acceptable salt thereof to improve glycemic control in a patient in need thereof, comprising a) Determine homeostatic model assessment (HOMA) 2-B status of the patient wherein the determination comprises i. Obtaining or having obtained a biological sample from the patient; ii. performing or having performed a HOMA 2-B assessment on the sample; c) If the patient’s HOMA 2-B is less than one (C-Peptide) then administer an effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, as a first line type 2 diabetes pharmaceutical treatment; and Wherein such treatment are administered at least 26 weeks.

2. A method of Claim 1 wherein the the treatment are administered at least 52 weeks.

3. A method as claimed by any one of Claims 1 or 2 wherein the patient has prediabetes.

4. A method as claimed by any one of Claims 1 to 3 wherein the effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, is administered once weekly.

5. A method as claimed by any one of Claims 1 to 4 wherein the effective amount of tirzepatide is selected from the group conisisting of 2.5mg, 5mg, 7.5mg, lOmg, 12.5mg, and 15 mg.

6. A method as claimed by any one of Claims 1 to 5 wherein the effective amount of tirzepatide, is selected from the group consisting of 5mg, lOmg, and 15mg.

7. A method as claimed by any one of Claims 1 to 6 wherein tirzepatide, or a pharmaceutically acceptable salt thereof, is a monotherapy pharmaceutical for treating glycemic control.

8. A method for treating or preventing type 2 diabetes in a patient with low H0MA2-B (C-Peptide), comprising administering a therapeutically effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, wherein the tirzepatide, or pharmaceutically acceptable salt thereof is the first line type 2 diabetes treatment.

9. A method as claimed by claim 8 wherein the treatment continues for at least 26 weeks.

10. A method as claimed by any one of Claims 8 and 9 wherein the treatment continues for at least 52 weeks.

11. A method as claimed by any one of Claims 8 to 10 wherein the treatment excludes metformin.

12. A method as claimed by any one of Claims 8 to 11 wherein the patient has prediabetes or at least 2 risk factors selected from the group consisisting of excess abdominal fat, obesity, sedentary lifestyle, family history, over the age of 45, gestational diabetes, and polycystic ovary syndrome.

13. A method as claimed by any one of Claims 8 to 12 wherein the patient has prediabetes.

14. A method as claimed by any one of Claims 8 to 13 wherein HbAlc after 26 weeks treatment is 6% or less.

15. A method of treating or preventing type 2 diabetes comprising

Administering a therapeutically effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to a human subject with low H0MA2-B, wherein the treatment continues for at least 26 weeks.

16. A method as claimed by Claim 15 wherein the treatment continues at least 52 weeks.

17. A method as claimed by any one of Claims 15 to 16 wherien the tirzepatide, or pharmaceutically acceptable salt thereof, is administered as a first line type 2 diabetes pharmaceutical treatment.

18. A method as claimed by any one of Claims 15 to 17 wherein the treatment excludes using metformin.

19. A method as claimed by any one of claims 15 to 18 wherein the treatment consists of tirzepatide, or a pharmaceutically acceptable salt thereof, as a type 2 diabetes pharmaceutical monotherapy.

20. A method as claimed by any one of Claims 15 to 19 wherein the H0MA2-B is less than 1.

21. A method as claimed by any one of Claims 15 to 19 wherein the H0MA2-B is in the lowest quartile of the standardized population.

22. A method for managing glycemic control in a patient with long-standing type 2 diabetes and using basal insulin treatment to manage glycemic control, comprising administering an effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, once weekly to such patient for at least 52 weeks.

23. A method as claimed by Claim 22 wherein the patient was diagnosed with type 2 diabetes more than 13 years prior to treatment with tirzepatide.

24. A method as claimed by any one of Claims 22 to 23 wherein the basal insulin treatment decreases during the treatment period.

25. A method as claimed by any one of Claims 22 to 24 wherein the basal insulin treatment is eliminated during the treatment period.

26. A method as claimed by any one of Claims 22 to 25 wherein the tirzepatide effective amount is selected from the group consisting of 10 and 15 mg.

27. A method as claimed by any one of Claims 22 to 26 wherein 15 mg tirzepatide is administered once weekly.

28. A method as claimed by any one of Claims 22 to 27 wherein tirzepatide is administered subcutaneously.

29. A method as claimed by any one of Claims 22 to 28 wherein a patient managing glycemic control has an HbAlc of 7.0 or less.

30. A method as claimed by any one of Claims 22 to 29 wherein the treatment continues for one calendar year.

31. A method as claimed by any one of Claims 22 to 29 wherein the treatment continues for at least 18 months.