Therapeutic use of tilepoptide

Abstract

The present invention relates to the therapeutic use of tilpotitide. The present invention relates to methods of treating, preventing or delaying cognitive related disorders, such as cognitive decline, cognitive impairment or dementia. The invention also relates to methods of treating, preventing or delaying heart failure, such as ejection fraction retention type heart failure (HFpEF) or ejection fraction reduction type heart failure (HFrEF).

Description

This application is a divisional application of the patent application for invention with the application date of January 22, 2021, application number 202180025864.7, and invention title "Therapeutic Use of Tirzepatide". Technical Field

[0001] The present invention relates to the field of medicine. Methods are provided for treating, preventing or delaying disorders related to cognition, such as cognitive decline, cognitive impairment or dementia. Methods are provided for treating, preventing or delaying heart failure. Background Art

[0002] Patients with type 2 diabetes mellitus (T2DM) often suffer from various comorbidities, including cognitive problems such as cognitive decline, cognitive impairment or dementia. The likelihood of a patient with diabetes developing cognitive decline, mild cognitive impairment or dementia is 1.5 to 2 times that of the non-diseased population. This relationship is independent of other risk factors for cognitive dysfunction and results in a prevalence of 13% in diabetic patients aged 65 - 74 years and 24% in patients aged 75 years or older. A single cause for the high risk of cognitive dysfunction in diabetic patients has not been identified. The possibility that certain diabetes therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists, may be beneficial to cognitive function has been proposed and is being investigated. See, for example, GD Femminella et al., Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomized controlled trial (ELAD study), 20 Trials 191 (2019). However, there is still a need for therapies for treating, preventing or delaying cognitive decline, cognitive impairment or dementia, including in patients with T2DM.

[0003] Patients with type 2 diabetes mellitus (T2DM) are at risk of developing heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). See, e.g., J. Ho et al., Predictors of New-Onset Heart Failure; Circulation: Heart Failure 6:279–286 (2013). Current treatments for HFpEF may include lifestyle modifications to induce weight loss and administration of agents for symptomatic relief of comorbid conditions. Bariatric surgery has shown some benefits in patients with HFpEF. See, e.g., Mikhalkova et al., Obesity (2018). Despite the increasing incidence of HFpEF, effective treatment options have been largely unsuccessful. See, e.g., Zheng et al., Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis, Heart. 104(5):407–415 (March 2018). There are currently no approved drug treatments for HFpEF. Therapies are needed to treat, prevent, or delay HFpEF. Therapies are needed to treat, prevent, or delay HFrEF. Summary of the Invention

[0004] The present invention provides methods for treating, preventing, or delaying cognitive impairment, such as cognitive decline, cognitive impairment, or dementia.

[0005] Accordingly, the present invention provides a method for treating, preventing, or delaying cognitive impairment in a patient or retarding its progression, which comprises administering to the patient a therapeutically effective amount of tirzepatide once a week.

[0006] In another aspect, the present invention provides a method for preventing or delaying cognitive decline in a patient, which comprises administering to the patient a therapeutically effective amount of tirzepatide once a week.

[0007] In another aspect, the present invention provides a method for improving glycemic control and treating, preventing, or delaying cognitive decline in a patient with type 2 diabetes mellitus, which comprises administering to the patient a therapeutically effective amount of tirzepatide once a week.

[0008] In another aspect, the present invention provides a method for improving glycemic control in a patient with type 2 diabetes mellitus who is at risk of cognitive decline, which comprises administering to the patient a therapeutically effective amount of tirzepatide once a week, wherein the method reduces the risk of the patient developing cognitive decline.

[0009] On the other hand, the present invention provides tirzepatide for treating, preventing, or delaying the development of cognitive impairment in a patient, including administering a therapeutically effective amount of tirzepatide to the patient once a week.

[0010] On the other hand, the present invention provides the use of tirzepatide for preparing a medicament for treating, preventing, or delaying the development of cognitive impairment in a patient, which includes administering a therapeutically effective amount of tirzepatide to the patient once a week.

[0011] The present invention provides a method for treating, preventing, or delaying heart failure, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0012] Accordingly, the present invention provides a method for treating, preventing, or delaying the development of HFpEF in a patient, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0013] Accordingly, the present invention provides a method for treating, preventing, or delaying the development of HFrEF in a patient, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0014] On the other hand, the present invention provides a method for preventing or delaying HFpEF in a patient, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0015] On the other hand, the present invention provides a method for preventing or delaying HFrEF in a patient, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0016] On the other hand, the present invention provides a method for improving glycemic control in patients with type 2 diabetes and treating, preventing, or delaying HFpEF in a patient, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0017] On the other hand, the present invention provides a method for improving glycemic control in patients with type 2 diabetes and treating, preventing, or delaying HFrEF in a patient, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0018] On the other hand, the present invention provides a method for improving glycemic control in a patient with type 2 diabetes and at risk of HFpEF, which includes administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week, wherein the method reduces the risk of the patient developing HFpEF.

[0019] In another aspect, the present invention provides a method for improving glycemic control in patients with type 2 diabetes and at risk of HFrEF, which comprises administering to the patient an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the risk of the patient developing HFrEF.

[0020] In another aspect, the present invention provides a method for improving weight management in patients with obesity and at risk of HFpEF, which comprises administering to the patient an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the risk of the patient developing HFpEF.

[0021] In another aspect, the present invention provides a method for treating HFpEF in patients at risk of HFpEF, which comprises administering to the patient an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week, wherein the patient's weight is within the patient's normal weight range.

[0022] In another aspect, the present invention provides a method for improving weight management in patients with obesity and at risk of HFrEF, which comprises administering to the patient an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the risk of the patient developing HFrEF.

[0023] In another aspect, the present invention provides tirzepatide or a pharmaceutically acceptable salt thereof for treating, preventing HFpEF in a patient or delaying its development, comprising administering to the patient an effective amount of tirzepatide once a week.

[0024] In another aspect, the present invention provides tirzepatide or a pharmaceutically acceptable salt thereof for treating, preventing HFrEF in a patient or delaying its development, comprising administering to the patient an effective amount of tirzepatide once a week.

[0025] In another aspect, the present invention provides the use of tirzepatide or a pharmaceutically acceptable salt thereof for preparing a medicament for treating, preventing HFpEF in a patient or delaying its development, comprising administering to the patient a therapeutically effective amount of tirzepatide once a week.

[0026] In another aspect, the present invention provides the use of tirzepatide for preparing a medicament for treating, preventing HFrEF in a patient or delaying its development, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week. Detailed Description

[0027] US9474780 describes and claims tirzepatide. As used herein, the term "tirzepatide" refers to any GIP / GLP-1 receptor agonist having the amino acid sequence of SEQ ID NO:1, including any protein that is the subject of a regulatory submission for approval of a GIP / GLP-1 receptor agonist product - which is wholly or in part dependent on data regarding tirzepatide submitted by Eli Lilly and Company to a regulatory agency, regardless of whether the party seeking approval of the protein actually identifies the protein as tirzepatide or uses some other term. Tirzepatide agonizes the GIP / GLP-1 receptor, thereby stimulating insulin synthesis and secretion, and has been shown to provide improved glycemic control in patients with T2DM.

[0028] Cognitive decline The development or progression of cognitive decline can be reflected in scores generated by performing measurements of cognitive status, such as the Montreal Cognitive Assessment (MoCA) and the Digit Symbol Substitution Test (DSST).

[0029] The MOCA is a cognitive screening test that has been validated in the context of mild cognitive impairment and subsequently adopted in many clinical settings. The test consists of a 1-page, 30-item questionnaire that is designed to be administered in approximately 10 minutes in the participant's first language using a validated translation. It assesses seven cognitive domains, including short-term memory, visuospatial ability, executive function, attention, concentration, working memory, and language. See, e.g., Nasreddine ZS et al., The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J. Am. Geriatr. Soc. 2005; 53(4):695-9; Pendlebury ST et al., Underestimation of cognitive impairment by Mini-Mental State Examination versus the Montreal Cognitive Assessment in patients with transient ischemic attack and stroke: a population-based study. Stroke 2010; 41(6):1290-3. The MOCA score is equal to the number of items answered correctly out of 30, with an additional 1 point added if the individual reports ≤12 years of education. Control validation studies in cognitively normal individuals have reported a mean MOCA score of 27.4 with a standard deviation of 2.2. However, population-based studies of presumably cognitively intact people have reported much lower mean scores. See, e.g., Rossetti HC et al., Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology 2011; 77(13):1272-5.

[0030] The DSST is a subtest of the Wechsler Adult Intelligence Scale (3rd Edition) and assesses a wide range of cognitive domains, including visuomotor speed and coordination, learning ability, attention, concentration, and short-term memory. See Wechsler D, Manual for the Wechsler Adult Intelligence scale. NY, NY. (1955); D W. The Wechsler Adult Intelligence Scale - Revised. NY, NY: The Psychological Corporation (1981). It consists of nine rows of randomly ordered symbols with blank squares below and a lookup table at the top of the page that pairs each symbol with a number. The respondent fills in the corresponding number in the space below each symbol as quickly as possible within a 2-minute time limit. The score is the number of consecutive digit-symbol pairs completed correctly within 2 minutes, and the maximum possible score is 135. It has been widely used to measure the cognitive function of cognitively intact individuals with and without diabetes, and validation studies have demonstrated its ability to predict future cognitive dysfunction and disability; it is relatively easy to administer; has no specific language; and its scores are related to measures of physical function and future cognitive decline. See, e.g., Rosano C et al., Association Between Lower Digit Symbol Substitution Test Score and Slower Gait and Greater Risk of Mortality and of Developing Incident Disability in Well-Functioning Older Adults, J. Am. Geriatr. Soc. (2008); Knopman D et al., Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology. 56(1):42-8 (2001). When the DSST is used in randomized controlled trials involving cognitively intact populations with glucose metabolism disorders, the mean baseline score ranges from 36 to 52.See Cukierman-Yaffe T et al., Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. The lancet Diabetes & endocrinology 2014;2(7):562-72; Launer LJ et al., Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORDMIND): a randomised open-label substudy. Lancet Neurol. (2011);10(11):969-77.

[0031] Previous studies have shown that the normal range of cognitive test scores may vary by country. Rossetti HC et al., Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample. Neurology 2011;77(13):1272-5; Thomann AE et al., The Montreal Cognitive Assessment: Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples. J. Alzheimer’s Dis. 2018;64(2):643-55. Therefore, when assessing substantive decline in a group that includes individuals from multiple countries, it may be desirable to standardize each individual's score at each time point to the mean baseline score and standard deviation of the values achieved within their country, rather than the mean and standard deviation of the entire group.

[0032] Previous studies have also noted that among middle-aged individuals, cognitive test scores decline very slowly over time, but some individuals experience a faster decline than others. See Cukierman-Yaffe T et al., Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. The lancet Diabetes & endocrinology 2014;2(7):562-72; Proust-Lima C et al., Sensitivity of four psychometric tests to measure cognitive changes in brain aging-population-based studies. Am. J. Epidemiol. 2007;165(3):344-50. These and other studies support the use of a threshold-based definition of a decline of 1.5 standard deviations or more from baseline. See also Group SR et al., Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA 2019;321(6):553-61; Group SR. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N. Engl. J. Med. 2015; Biessels GJ et al., Rationale and design of the CAROLINA(R)-cognition substudy: a randomised controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus. BMC Neurol. 2018;18(1):7.

[0033] As used herein, the term "cognitive impairment" refers to any condition involving impairment of a person's cognitive functions, such as memory, the ability to learn new things, the ability to concentrate, and / or difficulty in making decisions that affect a person's daily life. Such impairment ranges from mild cognitive impairment (MCI) to mild, moderate, and severe dementia. MCI refers to a stage of cognitive impairment between expected cognitive changes consistent with aging and mild dementia, and may be characterized by a slight but detectable and measurable decline in cognitive abilities, including memory and thinking skills, but without loss of the ability to perform daily activities. More severe impairment or dementia is associated with loss of the ability to perform daily activities and, depending on the severity, with loss of the ability to read, write, and / or understand the meaning or significance of things.

[0034] The methods provided herein may be most effective in patients at relatively high risk of developing cognitive decline. In certain embodiments, such patients are those having one or more of the following: T2DM; hypertension; elevated cholesterol and / or obesity.

[0035] In certain embodiments, these patients have established cardiovascular disease; and / or one or more risk factors for major adverse cardiovascular events.

[0036] Heart failure Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction - the percentage of the volume of blood ejected from the left ventricle per heartbeat divided by the volume of blood in the left ventricle at its maximum filling - is normal (defined as greater than 50%). Despite the increasing incidence of HFpEF, efforts to effectively treat HFpEF have been largely unsuccessful.

[0037] Conventionally, heart failure has been treated with various medications to treat comorbid symptoms. Such treatments include alpha-adrenergic agonists, beta-adrenergic agonists, calcium channel antagonists, cardiac glycosides, diuretics, nitrates, phosphodiesterase inhibitors, prazosin, and various vasodilators. These treatments are associated with unwanted side effects. For example, alpha-adrenergic agonists may be associated with edema in peripheral tissues. Certain treatments are associated with desensitization to the drug, such that the treatment becomes ineffective. There remains a need for HFpEF therapies with an acceptable drug side effect profile. In addition, there is a need for HFrEF therapies with an acceptable drug side effect profile.

[0038] As used herein, the term "substantial cognitive decline" or "SCD" refers to a significant decline in a subject's score of 1.5 standard deviations or greater on a standardized cognitive assessment, such as the MoCA or DSST.

[0039] As used herein, the terms "country-standardization", "country-standardized", etc. refer to the normalization of cognitive function scores performed as follows: calculating the baseline mean and standard deviation of scores within each country; and using these baseline mean and standard deviation to calculate the standardized MOCA and DSST scores of each participant at that time point by subtracting the country-specific baseline mean score from the score of each individual at each time point and dividing the difference by the country-specific baseline standard deviation.

[0040] As used herein, the term "major adverse cardiovascular event" refers to cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. These events are sometimes also referred to as MACE or MACE 3 events. The first occurrence of any one of these events is a commonly used composite endpoint in CVOTs.

[0041] When used in the context of major adverse cardiovascular events herein, the term "risk factor" refers to characteristics of patients with T2DM that are understood to increase their risk of major adverse cardiovascular events. Such risk factors specifically include any one of the following: using tobacco (any form of tobacco); using at least 1 approved lipid-lowering therapy (such as statins, such as atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin; PCSK9 inhibitors, such as evolocumab or alirocumab; and ezetimibe) to treat hypercholesterolemia or documented untreated low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol / L (130 mg / dL) within the past 6 months; documented treated or untreated high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol / L (40 mg / dL) in men and < 1.3 mmol / L (50 mg / dL) in women or triglycerides ≥ 2.3 mmol / L (200 mg / dL) within the past 6 months; using at least 1 blood pressure medication to treat hypertension (such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), thiazide diuretics, and dihydropyridine calcium channel blockers) or untreated systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 95 mmHg; measuring a waist-to-hip ratio > 1.0 in men and > 0.8 in women.

[0042] As used herein, "improved weight management" refers to a patient's weight being within or close to the clinically defined normal weight range for the patient. The "normal weight" for a particular patient can be determined by a clinician considering applicable factors known to skilled clinicians. Generally, improved weight management refers to a patient losing weight to reach a weight within or closer to the patient's desired weight range. As used herein, the "normal weight range" should be the weight that a skilled clinician determines to be the normal weight for a particular patient. The normal weight range can vary depending on the patient's height and other factors considered by the skilled clinician in weight assessment.

[0043] As used herein, terms such as "treat" are intended to include slowing or attenuating the progression of a disease, condition, or disorder. These terms also include alleviating, improving, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if the progression of the disorder or condition itself is not slowed or reversed. As used herein, terms such as "prevent" are intended to include avoiding the onset of a disease, condition, disorder, or symptom. As used herein, terms such as "delay" are intended to include increasing the period that exists until the onset of a disease, condition, disorder, or symptom.

[0044] When used in combination with multiple outcomes herein, the term "composite" refers to the first occurrence of any outcome.

[0045] As used herein, the term "hazard ratio" refers to a measure of the relative rate of progression to an endpoint compared to a control group. In an outcome-based clinical trial, a reduction in the hazard ratio of the treatment group compared to the control group indicates that the therapy used in the treatment group reduces the risk of the endpoint (major adverse cardiovascular events in the context of the studies described herein).

[0046] A "therapeutically effective amount" is the amount of tirzepatide for the methods and uses of the present invention or a pharmaceutical composition comprising tirzepatide for the methods and uses of the present invention that causes a biological or medical response in a patient that is sought by a researcher, physician, or other clinician or the desired therapeutic effect on the patient. The effective amount of tirzepatide can vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of tirzepatide to cause the desired response in the individual. The effective amount is also the amount where the therapeutic beneficial effects exceed any toxic or detrimental effects. In certain embodiments, the therapeutically effective amount of tirzepatide for the methods described herein is selected from 5, 10, and 15 mg. In certain embodiments, the therapeutically effective amount of tirzepatide is 5.0 mg. In certain embodiments, the therapeutically effective amount of tirzepatide is 10.0 mg. In a preferred embodiment, the therapeutically effective amount of tirzepatide is 15.0 mg.

[0047] Additional embodiments of the present invention are described below: Cognitive impairment A method for treating, preventing or delaying the development of cognitive impairment in a patient, which comprises administering to the patient a therapeutically effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week. In one embodiment, the cognitive impairment is selected from MCI and dementia.

[0048] A method for preventing or delaying cognitive decline in a patient, which comprises administering to the patient a therapeutically effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week.

[0049] A method for improving glycemic control and treating, preventing or delaying cognitive decline in a patient with type 2 diabetes, which comprises administering to the patient a therapeutically effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week.

[0050] In one embodiment, the method reduces the risk of cognitive decline in the patient.

[0051] A method for improving glycemic control in a patient with type 2 diabetes, which comprises administering to the patient a therapeutically effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the risk of cognitive decline in the patient.

[0052] The method of any of the above embodiments, wherein the patient has type 2 diabetes.

[0053] The method of any of the above embodiments, wherein the patient has one or more of the following: T2DM; hypertension; elevated cholesterol and obesity.

[0054] In one embodiment, the patient has: multiple cardiovascular risk factors without a diagnosis of cardiovascular disease; or a diagnosed cardiovascular disease.

[0055] In one embodiment, the risk factors for cardiovascular disease are selected from: current use of tobacco (any form of tobacco); treatment of hypercholesterolemia with at least 1 approved lipid-lowering therapy or documented untreated low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol / L (130 mg / dL) in the past 6 months; documented treated or untreated high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol / L (40 mg / dL) in men and < 1.3 mmol / L (50 mg / dL) in women or triglycerides ≥ 2.3 mmol / L (200 mg / dL) in the past 6 months; treatment of hypertension with at least 1 blood pressure medication or untreated systolic blood pressure (SBP) ≥ 140 mm Hg or diastolic blood pressure (DBP) ≥ 95 mmHg; measured waist-to-hip ratio > 1.0 in men and > 0.8 in women.

[0056] In one embodiment, the cognitive impairment is selected from MCI and dementia.

[0057] In one embodiment, the risk of cognitive decline in a patient is reduced by at least about 14%.

[0058] In one embodiment, the risk of major adverse cardiovascular events is reduced by at least about 10%.

[0059] In one embodiment, the risk of major adverse cardiovascular events is reduced by at least about 11%.

[0060] In one embodiment, the risk of major adverse cardiovascular events is reduced by about 12%.

[0061] In one embodiment, the risk of occurrence of a composite of the following outcomes is reduced: cognitive decline or death.

[0062] In one embodiment, the risk of occurrence of a composite of the following outcomes is reduced: cognitive decline or stroke.

[0063] In one embodiment, the risk of occurrence of a composite of the following outcomes is reduced: cognitive decline, stroke, or transient ischemic attack.

[0064] In one embodiment, the risk of occurrence of a composite of the following outcomes is reduced: cognitive decline, stroke, transient ischemic attack, or death.

[0065] In one embodiment, the risk of cardiovascular death is lower.

[0066] In one embodiment, the risk of non-fatal stroke is lower.

[0067] In one embodiment, the risk of non-fatal myocardial infarction is lower.

[0068] In one embodiment, the risk of occurrence of a composite of the following outcomes is reduced: diabetic retinopathy requiring laser, anti-VEGF therapy, or vitrectomy; clinical proteinuria; a 30% decline in eGFR; or chronic kidney replacement therapy.

[0069] A method of treating, preventing, or delaying the development of cognitive impairment in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharmaceutically acceptable salt thereof once a week. In one embodiment, the cognitive impairment is selected from MCI and dementia.

[0070] In one embodiment, the amount of tirzepatide is selected from about 5.0 mg, about 10.0 mg, and about 15.0 mg.

[0071] In one embodiment, the amount of tirzepatide is about 5.0 mg.

[0072] In one embodiment, the amount of tirzepatide is about 10.0 mg.

[0073] In one embodiment, the amount of tirzepatide is about 15.0 mg.

[0074] In one embodiment, the once-weekly administration of tirzepatide or a pharmaceutically acceptable salt thereof continues for at least 2 years.

[0075] In one embodiment, the once-weekly administration of tirzepatide or a pharmaceutically acceptable salt thereof continues for at least 3 years.

[0076] In one embodiment, the once-weekly administration of tirzepatide or a pharmaceutically acceptable salt thereof continues for at least 4 years.

[0077] In one embodiment, the once-weekly administration of tirzepatide or a pharmaceutically acceptable salt thereof continues for about 5 years.

[0078] In one embodiment, the once-weekly administration of tirzepatide or a pharmaceutically acceptable salt thereof continues for at least 5.4 years.

[0079] In one embodiment, tirzepatide or a pharmaceutically acceptable salt thereof is administered using a dose escalation regimen.

[0080] In one embodiment, standard care for reducing the risk of major adverse cardiovascular events is also administered to the patient.

[0081] In one embodiment, the maximum tolerated dose of an ACE inhibitor is also administered to the patient.

[0082] In one embodiment, the maximum tolerated dose of an ARB is also administered to the patient.

[0083] In one embodiment, a β-blocker is also administered to the patient.

[0084] In one embodiment, a calcium channel blocker is also administered to the patient.

[0085] In one embodiment, a diuretic is also administered to the patient.

[0086] In one embodiment, an antithrombotic agent is also administered to the patient.

[0087] In one embodiment, aspirin is also administered to the patient.

[0088] In one embodiment, statins are also administered to the patient.

[0089] Tirzepatide or a pharmaceutically acceptable salt thereof, which is for any of the above embodiments.

[0090] Use of tirzepatide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for any of the above embodiments.

[0091] Heart failure A method of treating, preventing heart failure in a patient or delaying its progression, which comprises administering to the patient a therapeutically effective amount of teprotide or a pharmaceutically acceptable salt thereof once a week. In one embodiment, the heart failure is selected from HFpEF and HFrEF.

[0092] A method of preventing or delaying heart failure in a patient, which comprises administering to the patient a therapeutically effective amount of teprotide or a pharmaceutically acceptable salt thereof once a week.

[0093] A method of improving glycemic control and treating, preventing or delaying heart failure in a patient with type 2 diabetes, which comprises administering to the patient a therapeutically effective amount of teprotide or a pharmaceutically acceptable salt thereof once a week.

[0094] In one embodiment, the method reduces the risk of the patient developing HFpEF. In one embodiment, the method reduces the risk of the patient developing HFrEF.

[0095] A method of improving glycemic control in a patient with type 2 diabetes, which comprises administering to the patient a therapeutically effective amount of teprotide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the risk of the patient developing cognitive decline.

[0096] The method of any of the above embodiments, wherein the patient has type 2 diabetes.

[0097] The method of any of the above embodiments, wherein the patient has one or more of the following: T2DM; hypertension; elevated cholesterol and obesity.

[0098] In one embodiment, the patient has: multiple cardiovascular risk factors without a diagnosed cardiovascular disease; or a diagnosed cardiovascular disease.

[0099] In one embodiment, the risk factors for cardiovascular disease are selected from: using tobacco (any form of tobacco); using at least 1 approved lipid-lowering therapy to treat hypercholesterolemia or having well-documented untreated low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol / L (130 mg / dL) in the past 6 months; having well-documented treated or untreated high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol / L (40 mg / dL) in men and < 1.3 mmol / L (50 mg / dL) in women or triglycerides ≥ 2.3 mmol / L (200 mg / dL) in the past 6 months; using at least 1 blood pressure medication to treat hypertension or having untreated systolic blood pressure (SBP) ≥ 140 mm Hg or diastolic blood pressure (DBP) ≥ 95 mmHg; measuring a waist-to-hip ratio > 1.0 in men and > 0.8 in women.

[0100] In one embodiment, heart failure is selected from HFpEF and HFrEF.

[0101] In one embodiment, the patient's 6-minute walk test improves. In one embodiment, the patient's 6-minute walk test confirms an improvement in exercise capacity.

[0102] In one embodiment, the patient's Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improves. In one embodiment, the improved KCCQ-CSS is associated with a net clinical benefit.

[0103] In one embodiment, the patient's risk of heart failure is reduced by at least about 14%.

[0104] In one embodiment, the risk of heart failure is reduced by at least about 10%.

[0105] In one embodiment, the Pro-C3 inflammatory marker is reduced. In one embodiment, the Pro-C3 inflammatory marker is reduced to a clinically desired level.

[0106] In one embodiment, the CRP level is reduced. In one embodiment, the CRP level is reduced to a clinically desired level.

[0107] In one embodiment, the risk of occurrence of the following composite outcome is reduced: hospitalization or death due to HFpEF.

[0108] In one embodiment, in a patient treated with an effective amount of teprotide or a pharmaceutically acceptable salt thereof, the risk of death or hospitalization due to HFpEF is reduced.

[0109] In one embodiment, the risk of occurrence of the following composite outcome is reduced: HFpEF or cognitive decline.

[0110] In one embodiment, the risk of occurrence of the following composite outcome is reduced: cognitive decline, HFpEF or HFrEF.

[0111] In one embodiment, the risk of occurrence of the following composite outcome is reduced: cognitive decline, HFpEF or death.

[0112] A method of treating, preventing or delaying the development of heart failure in a patient, which comprises administering to the patient a therapeutically effective amount of teprotide or a pharmaceutically acceptable salt thereof once a week. In one embodiment, heart failure is selected from HFpEF and HFrEF.

[0113] In one embodiment, the amount of tirzepatide is selected from about 5.0 mg, about 10.0 mg, and about 15.0 mg.

[0114] In one embodiment, the amount of tirzepatide is about 5.0 mg.

[0115] In one embodiment, the amount of tirzepatide is about 10.0 mg.

[0116] In one embodiment, the amount of tirzepatide is about 15.0 mg.

[0117] In one embodiment, the patient is at least 50 years old. In one embodiment, the patient is at least 65 years old.

[0118] In one embodiment, the once-weekly administration of tirzepatide continues for at least 2 years.

[0119] In one embodiment, the once-weekly administration of tirzepatide continues for at least 3 years.

[0120] In one embodiment, the once-weekly administration of tirzepatide continues for at least 4 years.

[0121] In one embodiment, the once-weekly administration of tirzepatide continues for about 5 years.

[0122] In one embodiment, the once-weekly administration of tirzepatide continues for at least 5.5 years.

[0123] In one embodiment, tirzepatide or a pharmaceutically acceptable salt thereof is administered using a dose escalation regimen.

[0124] In one embodiment, standard of care for reducing the risk of major adverse cardiovascular events is also administered to the patient.

[0125] In one embodiment, standard of care for treating the symptoms of comorbid conditions of HFrEF is also administered to the patient.

[0126] In one embodiment, the maximum tolerated dose of an ACE inhibitor is also administered to the patient.

[0127] In one embodiment, the maximum tolerated dose of an ARB is also administered to the patient.

[0128] In one embodiment, a β-blocker is also administered to the patient.

[0129] In one embodiment, a calcium channel blocker is also administered to the patient.

[0130] In one embodiment, a diuretic is also administered to the patient.

[0131] In one embodiment, an antithrombotic agent is also administered to the patient.

[0132] In one embodiment, aspirin is also administered to the patient.

[0133] In one embodiment, statins are also administered to the patient.

[0134] Tirzepatide or a pharmaceutically acceptable salt thereof, which is used in any of the above embodiments.

[0135] Use of tirzepatide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for any of the above embodiments.

[0136] Further embodiments are described in the following examples, which should not be considered restrictive. Examples

[0137] The inclusion criteria listed in Table 1 below were designed to include participants similar to those seen in typical diabetes practice, having different cardiovascular risk factors or diagnosed cardiovascular disease: Table 1. Inclusion criteria.

[0138] The study was designed to consist of a screening visit and a subsequent single-blind 3-week placebo lead-in period. Thereafter, patients were randomly assigned to tirzepatide 5, 10, or 15 mg (administered using an escalating dose regimen) or placebo, and followed up at approximately 6-month intervals. Patients were followed until approximately 1200 patients had experienced the primary endpoint event, as adjudicated as such.

[0139] Analysis included assessing the effect of tirzepatide on cognitive decline, as measured by implementing two different cognitive tests - MOCA and DSST - at baseline and at 2 years, 5 years, and the end-of-study visit. The MOCA and DSST methods were described in more detail above.

[0140] The primary cognitive outcome was nationally standardized substantial cognitive decline (SCD), which was defined as a decrease in the MOCA or DSST score of ≥1.5 standard deviations from the individual baseline score. National standardization was achieved as follows: First, the baseline mean and standard deviation of the MOCA and DSST scores were calculated within each country. These baseline means and standard deviations were used to calculate the standardized MOCA and DSST scores for each participant at each time point. This was done by subtracting the country-specific baseline mean score from the score of the individual at that time point and dividing the difference by the country-specific baseline standard deviation. Additional cognitive outcomes included the composite of SCD with death, stroke, stroke or TIA, and stroke, TIA or death, and the change in standardized MOCA and DSST scores over time.

[0141] Cognitive analyses were restricted to participants with baseline MOCA or DSST scores and at least 1 follow-up score of the same type.

[0142] Continuous variables were summarized using mean and standard deviation, and binary variables were summarized using count and percentage. The Cox proportional hazards model was used to estimate the hazard of SCD and SCD-based composite outcomes with tirzepatide vs placebo before and after accounting for each individual's baseline standardized MOCA and DSST scores. The primary analysis was repeated using a discrete-time proportional odds logistic model to assess the sensitivity of the Cox model to the discrete nature of the outcomes due to the intermittent administration of cognitive tests. When indicated, the Cox model accounted for the competing risk of death. See Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association 1999;94:496-509. Differences in effects within subgroups were explored by including subgroup and subgroup-treatment interaction terms in the model. Finally, a repeated measures linear mixed effects model was used to estimate the effect of tirzepatide on the least mean squares of standardized MOCA and DSST scores, with standardized baseline scores as covariates, participants as random effects, and treatment, visit, and treatment-visit interaction as fixed effects. See Senn S. Change from baseline and analysis of covariance revisited. Stat Med 2006;25(24):4334-44.

[0143] Statistical analyses were performed using SAS software.

[0144] Example 2 A 52-week Phase 3 maximum tolerated dose (up to 15 mg / week) 6-minute walk test (“6MWT”) study was conducted in patients with obesity and HFpEF. A sample size of 500 patients was randomly assigned 1:1 to placebo and tirzepatide (maximum tolerated dose up to 15 mg / week). The study measured 6MWT, weight loss, Kansas City Cardiomyopathy Questionnaire (“KCCQ”), Churg-Strauss syndrome (“CSS”), left atrial volume index (“LAVI”), ectopic atrial tachycardia (“EAT”), and related magnetic resonance imaging (“MRI”) measurements, including, for example, left ventricular (“LV”) strain, LV mass index.

[0145] Example 3 In the Phase 2 study (GPGB), patients on tirzepatide at 15 mg / week showed improvements in C-reactive protein (“CRP”), vascular cell adhesion molecule 1 (“VCAM-1”), and intercellular adhesion molecule-1 (“ICAM-1”). Improvements in the biomarker of type III procollagen (“Pro-C3”) were observed in the 10 mg / week and 15 mg / week patient groups.

[0146] Sequence SEQ ID NO:1 Tirzepatide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS wherein X1 is Aib; X2 is Aib; the K at position 20 is chemically modified by conjugating the ε-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 to a C-terminal primary amide.

Claims

1. Use of tirzepatide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing or delaying the development of cognitive impairment in a patient, the method comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

2. The use according to claim 1, wherein the cognitive impairment is selected from MCI and dementia.

3. Use of tirzepatide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or delaying cognitive decline in a patient, the method comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

4. The use according to any one of claims 1 to 3, wherein the patient has type 2 diabetes.

5. Use of tirzepatide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving glycemic control and preventing or delaying cognitive decline in a patient with type 2 diabetes, the method comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week.

6. The use according to any one of claims 1 to 5, wherein the method reduces the risk of the patient developing cognitive decline.

7. Use of tirzepatide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving glycemic control in a patient with type 2 diabetes, the method comprising administering an effective amount of tirzepatide or a pharmaceutically acceptable salt thereof to the patient once a week, wherein the method reduces the risk of the patient developing cognitive decline.

8. The use according to any one of claims 1 to 7, wherein the risk of cognitive decline in the patient is reduced by approximately 14%.

9. The use according to any one of claims 1 to 8, wherein the combined risk of the patient experiencing the following outcomes is reduced: cognitive decline, stroke, transient ischemic attack or death.

10. The use according to any one of claims 1 to 9, wherein the therapeutically effective amount of tirzepatide is selected from approximately 5.0 mg, approximately 10.0 mg and approximately 15.0 mg.

11. The use according to claim 10, wherein the therapeutically effective amount of tirzepatide is approximately 15.0 mg.

12. The use according to any one of claims 1 to 11, wherein the once-weekly administration of tirzepatide continues for at least 2 years.

13. The use according to any one of claims 1 to 12, wherein the patient has: multiple cardiovascular risk factors without diagnosed cardiovascular disease; or diagnosed cardiovascular disease.

Images