Therapeutic uses of telpotide

Abstract

The present invention relates to a method for treating, preventing or delaying cognitive-related disorders, such as cognitive decline, cognitive impairment or dementia. The present invention also relates to a method for treating, preventing or delaying heart failure, such as heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF).

Description

[0001] The present invention relates to the field of medicine and provides a method for treating, preventing or delaying cognitive-related disorders, such as cognitive decline, cognitive impairment or dementia, and a method for treating, preventing or delaying heart failure.

[0002] Patients with type 2 diabetes mellitus (T2DM) frequently suffer from a variety of comorbidities, including cognitive problems such as cognitive decline, cognitive impairment, or dementia. Patients with diabetes are 1.5 to 2 times more likely to develop cognitive decline, mild cognitive impairment, or dementia than those without the disease. This relationship is independent of other risk factors for cognitive dysfunction and accounts for a prevalence of 13% in patients with diabetes aged 65-74 years and 24% in patients aged 75 years or older. No single cause for the increased risk of cognitive dysfunction in patients with diabetes has been identified. The possibility that certain diabetes therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists, may have a beneficial effect on cognitive function has been proposed and is being studied. See, e.g., 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) , 20Trials 191 (2019). However, there remains a need for therapies to treat, prevent, or delay cognitive decline, cognitive impairment, or dementia, including in patients with T2DM.

[0003] Patients with type 2 diabetes mellitus (T2DM) are at risk for developing heart failure with preserved ejection fraction (HFpEF) as well as 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 changes to induce weight loss and administration of symptom-relieving agents for comorbid conditions. Bariatric surgery has shown some benefit for patients with HFpEF. See, e.g., Mikhalkova et al., Obesity (2018). Despite the increasing prevalence 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 progression of HFpEF. Therapies are needed to treat, prevent, or delay progression of HFrEF.

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

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

[0006] In another aspect, the present invention provides a method for preventing or delaying cognitive decline in a patient, comprising administering a therapeutically effective amount of telpotide to the patient 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 patients with type 2 diabetes, comprising administering a therapeutically effective amount of telpotide to the patient once a week.

[0008] In another aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes and at risk of cognitive decline, comprising administering to the patient a therapeutically effective amount of telpotide once a week, wherein the method reduces the patient's risk of developing cognitive decline.

[0009] In another aspect, the present invention provides telpotide for use in treating, preventing or delaying the development of cognitive impairment in a patient, comprising administering a therapeutically effective amount of telpotide to the patient once a week.

[0010] In another aspect, the present invention provides a use of telpotide for preparing a medicament for treating, preventing or delaying the development of cognitive impairment in a patient, comprising administering a therapeutically effective amount of telpotide to the patient once a week.

[0011] The present invention provides a method for treating, preventing or delaying heart failure, which comprises administering an effective amount of telpotide 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, comprising administering an effective amount of telportide 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, comprising administering an effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0014] In another aspect, the present invention provides a method for preventing or delaying HFpEF in a patient, comprising administering an effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0015] In another aspect, the present invention provides a method for preventing or delaying HFrEF in a patient, comprising administering an effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0016] In another aspect, the present invention provides a method for improving blood sugar control and treating, preventing or delaying HFpEF in patients with type 2 diabetes, comprising administering an effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0017] In another aspect, the present invention provides a method for improving glycemic control and treating, preventing or delaying HFrEF in patients with type 2 diabetes, comprising administering an effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0018] In another aspect, the present invention provides a method for improving glycemic control in a patient with type 2 diabetes and at risk of HFpEF, comprising administering to the patient once a week an effective amount of telpotide or a pharmaceutically acceptable salt thereof, wherein the method reduces the patient's risk of developing HFpEF.

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

[0020] In another aspect, the present invention provides a method for improving weight management in a patient who is obese and at risk for HFpEF, comprising administering to the patient an effective amount of telpotide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the patient's risk of developing HFpEF.

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

[0022] In another aspect, the present invention provides a method for improving weight management in a patient who is obese and at risk for HFrEF, comprising administering to the patient an effective amount of telpotide 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 telpotide or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying the development of HFpEF in a patient, comprising administering an effective amount of telpotide to the patient once a week.

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

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

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

[0027] US9474780 describes and claims telpotide. As used herein, the term "telpotide" 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 seeking approval of a GIP / GLP-1 receptor agonist product that relies in whole or in part on data submitted to regulatory agencies by Eli Lilly and Company regarding telpotide, regardless of whether the party seeking approval of the protein actually identifies the protein as telpotide or uses some other terminology. Telpotide 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

[0029] The development or progression of cognitive decline may be reflected in scores generated by administering measures of cognitive status such as the Montreal Cognitive Assessment (MoCA) and the Digit Symbol Substitution Test (DSST).

[0030] The MOCA is a cognitive screening test that has been validated in cases of mild cognitive impairment and subsequently adopted in many clinical settings. The test contains a 1-page, 30-item questionnaire designed to be conducted 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 point added if the individual reports ≤ 12 years of education. Controlled validation studies in cognitively normal individuals have reported mean MOCA scores 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.

[0031] The DSST is a subtest of the Wechsler Adult Intelligence Scale (3rd edition) and assesses a wide range of cognitive domains, including visual-motor 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 rows of 9 randomly ordered symbols with blank squares below and a key at the top of the page to pair each symbol with a number. Respondents have 2 minutes to fill in the corresponding number in the space below each symbol as quickly as possible. The score is the number of consecutive number-symbol pairs completed correctly in 2 minutes, and the maximum possible score is 135. It has been widely used to measure cognitive function in cognitively intact individuals with and without diabetes, and validation studies have shown that it predicts future cognitive dysfunction and disability; is relatively easy to administer; has no specific language; and its scores correlate with 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 was used in randomized controlled trials involving cognitively intact people with impaired glucose metabolism, the mean baseline scores were 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 (ACCORD MIND): a randomised open-label substudy .Lancet Neurol. (2011); 10(11): 969-77.

[0032] Previous studies have shown that normal ranges for cognitive test scores may vary between countries. 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 value achieved within their country rather than to the mean and standard deviation of the entire group.

[0033] Previous studies have also noted that within a group of middle-aged individuals, cognitive test scores decline very slowly over time, but some individuals experience more rapid 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 decrease of 1.5 standard deviations or greater 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 randomized controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus . BMC Neurol. 2018; 18(1): 7.

[0034] The term "cognitive impairment" as used herein refers to any condition involving impairment of a person's cognitive function, such as difficulty with memory, learning new things, the ability to concentrate, and / or decision making that affects a person's daily life. Such impairments range from mild cognitive impairment (MCI) to mild, moderate, and severe dementia. MCI refers to a stage of cognitive impairment between the expected cognitive changes consistent with aging and mild dementia, and may be characterized by a slight but perceptible and measurable decline in cognitive abilities, including memory and thinking skills, but without a loss of the ability to engage in daily activities. More severe impairment or dementia is associated with a loss of the ability to perform daily activities and, depending on severity, is associated with a loss of the ability to read, write, and / or understand the meaning or importance of things.

[0035] 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 with one or more of: T2DM; hypertension; elevated cholesterol and / or obesity.

[0036] In certain embodiments, the patients have established cardiovascular disease; and / or one or more risk factors for major adverse cardiovascular events.

[0037] Heart failure

[0038] Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction—the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood that fills the left ventricle at maximum—is normal (defined as greater than 50%). Despite the increased prevalence of HFpEF, efforts to effectively treat HFpEF have been largely unsuccessful.

[0039] Conventionally, heart failure has been treated with various drugs 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 of peripheral tissues. Certain treatments are associated with desensitization to the drug, resulting in the failure of the treatment. There is still 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.

[0040] As used herein, the term "substantial cognitive decline" or "SCD" refers to a significant drop in a subject's score of 1.5 standard deviations or greater on a standardized cognitive assessment, such as the MoCA or DSST.

[0041] The terms "country-standardization," "country-standardized," and the like, as used herein, refer to normalization of cognitive function scores performed by calculating baseline means and standard deviations of scores within each country; and using these baseline means and standard deviations to calculate standardized MOCA and DSST scores for each participant at that time point by subtracting the country-specific baseline mean score from each individual's score at each time point and dividing the difference by the country-specific baseline standard deviation.

[0042] The term "major adverse cardiovascular events" as used herein 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 of these events is a commonly used composite endpoint in CVOT.

[0043] When used herein in connection with major adverse cardiovascular events, 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 of the following: current tobacco use (in any form); use of at least 1 approved lipid-lowering therapy (e.g., statins such as atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin; PCSK9 inhibitors such as evolocumab or amorobumab (alirocumab); and ezetimibe) in the past 6 months for treatment of hypercholesterolemia or documented untreated low-density lipoprotein cholesterol (LDL-C) ≥3.4 mmol / L (130 mg / dL); 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 in the past 6 months mmol / L (200mg / dL); use of 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; measured waist-to-hip ratio >1.0 for men and >0.8 for women.

[0044] As used herein, "improved weight management" refers to a patient's weight that is within or close to a clinically defined normal weight range for a patient. The "normal weight" for a particular patient can be determined by a clinician taking into account applicable considerations known to skilled clinicians. Typically, improved weight management refers to a patient losing weight to reach a weight that is within or closer to the patient's desired weight range. As used herein, a "normal weight range" should be a weight that a skilled clinician determines to be a normal weight for a particular patient. The normal weight range can vary depending on the patient's height and other factors that a skilled clinician considers in weight assessment.

[0045] As used herein, the terms "treating," "treating," and the like are intended to include slowing or attenuating the progression of a disease, condition, or disorder. These terms also include alleviating, ameliorating, 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, the terms "preventing," and the like are intended to include avoiding the onset of a disease, condition, disorder, or symptom. As used herein, the terms "delaying," and the like are intended to include increasing the period of time that exists until the onset of a disease, condition, disorder, or symptom.

[0046] When used in this article in conjunction with multiple outcomes, the term “composite” refers to the first occurrence of any one outcome.

[0047] The term "hazard ratio" as used herein 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 experimental group compared to the control group indicates that the therapy used in the experimental group reduces the risk of the endpoint (in the case of the studies described herein, major adverse cardiovascular events).

[0048] "Therapeutically effective amount" refers to the amount of telpotide used in the methods and uses of the present invention or a pharmaceutical composition comprising telpotide used in the methods and uses of the present invention that elicits the biological or medical response of the patient or the desired therapeutic effect on the patient that is being sought by the researcher, physician or other clinician. The effective amount of telpotide may vary depending on factors such as the disease state, age, sex and weight of the individual, and the ability of telpotide to elicit the desired response in the individual. An effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or detrimental effects. In certain embodiments, the therapeutically effective amount of telpotide used in the methods described herein is selected from 5, 10 and 15 mg. In certain embodiments, the therapeutically effective amount of telpotide is 5.0 mg. In certain embodiments, the therapeutically effective amount of telpotide is 10.0 mg. In a preferred embodiment, the therapeutically effective amount of telpotide is 15.0 mg.

[0049] Further embodiments of the present invention are described below:

[0050] Cognitive impairment

[0051] A method for treating, preventing or delaying the development of cognitive impairment in a patient, comprising administering a therapeutically effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week. In one embodiment, the cognitive impairment is selected from MCI and dementia.

[0052] A method for preventing or delaying cognitive decline in a patient, comprising administering a therapeutically effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0053] A method for improving blood sugar control and treating, preventing or delaying cognitive decline in patients with type 2 diabetes, comprising administering a therapeutically effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0054] In one embodiment, the method reduces the risk of a patient experiencing cognitive decline.

[0055] A method for improving glycemic control in a patient with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of telportide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the risk of cognitive decline in the patient.

[0056] The method of any of the above embodiments, wherein the patient has type 2 diabetes.

[0057] The method of any of the above embodiments, wherein the patient has one or more of: T2DM; hypertension; elevated cholesterol and obesity.

[0058] In one embodiment, the patient has: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0059] In one embodiment, risk factors for cardiovascular disease are selected from: current tobacco use (any form); use of at least 1 approved lipid-lowering therapy for hypercholesterolemia 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; use of at least 1 blood pressure medication for hypertension 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.

[0060] In one embodiment, the cognitive disorder is selected from MCI and dementia.

[0061] In one embodiment, the patient's risk of cognitive decline is reduced by at least about 14%.

[0062] In one embodiment, the risk of a major adverse cardiovascular event is reduced by at least about 10%.

[0063] In one embodiment, the risk of a major adverse cardiovascular event is reduced by at least about 11%.

[0064] In one embodiment, the risk of major adverse cardiovascular events is reduced by about 12%.

[0065] In one embodiment, the risk of a composite of the following outcomes is reduced: cognitive decline or death.

[0066] In one embodiment, the risk of a composite of the following outcomes is reduced: cognitive decline or stroke.

[0067] In one embodiment, the risk of a composite of the following outcomes is reduced: cognitive decline, stroke, or transient ischemic attack.

[0068] In one embodiment, the risk of a composite of the following outcomes is reduced: cognitive decline, stroke, transient ischemic attack, or death.

[0069] In one embodiment, the risk of cardiovascular death is low.

[0070] In one embodiment, the risk of non-fatal stroke is low.

[0071] In one embodiment, the risk of non-fatal myocardial infarction is low.

[0072] In one embodiment, the risk of a composite of the following outcomes is reduced: diabetic retinopathy requiring laser, anti-VEGF therapy, or vitrectomy; clinical proteinuria; a 30% decrease in eGFR; or chronic renal replacement therapy.

[0073] A method for treating, preventing or delaying the development of cognitive impairment in a patient, comprising administering a therapeutically effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week. In one embodiment, the cognitive impairment is selected from MCI and dementia.

[0074] In one embodiment, the amount of teilpotide is selected from about 5.0 mg, about 10.0 mg, and about 15.0 mg.

[0075] In one embodiment, the amount of teilpotide is about 5.0 mg.

[0076] In one embodiment, the amount of telpotide is about 10.0 mg.

[0077] In one embodiment, the amount of teilpotide is about 15.0 mg.

[0078] In one embodiment, the weekly administration of telpotide or a pharmaceutically acceptable salt thereof continues for at least 2 years.

[0079] In one embodiment, the weekly administration of telpotide or a pharmaceutically acceptable salt thereof continues for at least 3 years.

[0080] In one embodiment, the weekly administration of telpotide or a pharmaceutically acceptable salt thereof continues for at least 4 years.

[0081] In one embodiment, the weekly administration of telpotide or a pharmaceutically acceptable salt thereof continues for about 5 years.

[0082] In one embodiment, the once weekly administration of telpotide or a pharmaceutically acceptable salt thereof continues for at least 5.4 years.

[0083] In one embodiment, telpotide or a pharmaceutically acceptable salt thereof is administered using a dose escalation regimen.

[0084] In one embodiment, the patient is also administered standard of care for reducing the risk of major adverse cardiovascular events.

[0085] In one embodiment, the patient is also administered a maximum tolerated dose of an ACE inhibitor.

[0086] In one embodiment, the patient is also administered the maximum tolerated dose of an ARB.

[0087] In one embodiment, the patient is also administered a beta-blocker.

[0088] In one embodiment, a calcium channel blocker is also administered to the patient.

[0089] In one embodiment, a diuretic is also administered to the patient.

[0090] In one embodiment, an antithrombotic agent is also administered to the patient.

[0091] In one embodiment, aspirin is also administered to the patient.

[0092] In one embodiment, the patient is also administered a statin.

[0093] Tipoleptide or a pharmaceutically acceptable salt thereof, for use in any of the above embodiments.

[0094] Use of telpotide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in any one of the above embodiments.

[0095] Heart failure

[0096] A method for treating, preventing or delaying the development of heart failure in a patient, comprising administering a therapeutically effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week. In one embodiment, the heart failure is selected from HFpEF and HFrEF.

[0097] A method for preventing or delaying heart failure in a patient, comprising administering a therapeutically effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0098] A method for improving blood sugar control and treating, preventing or delaying heart failure in patients with type 2 diabetes, comprising administering a therapeutically effective amount of telportide or a pharmaceutically acceptable salt thereof to the patient once a week.

[0099] In one embodiment, the method reduces the risk of a patient developing HFpEF. In one embodiment, the method reduces the risk of a patient developing HFrEF.

[0100] A method for improving glycemic control in a patient with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of telportide or a pharmaceutically acceptable salt thereof once a week, wherein the method reduces the risk of cognitive decline in the patient.

[0101] The method of any of the above embodiments, wherein the patient has type 2 diabetes.

[0102] The method of any of the above embodiments, wherein the patient has one or more of: T2DM; hypertension; elevated cholesterol and obesity.

[0103] In one embodiment, the patient has: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0104] In one embodiment, risk factors for cardiovascular disease are selected from: current tobacco use (any form); use of at least 1 approved lipid-lowering therapy for hypercholesterolemia 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; use of at least 1 blood pressure medication for hypertension 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.

[0105] In one embodiment, the heart failure is selected from HFpEF and HFrEF.

[0106] In one embodiment, the patient's 6-minute walk test improves. In one embodiment, the patient's 6-minute walk test demonstrates improved exercise capacity.

[0107] In one embodiment, the patient's Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improves. In one embodiment, improved KCCQ-CSS is associated with a net clinical benefit.

[0108] In one embodiment, the patient's risk of heart failure is reduced by at least about 14%.

[0109] In one embodiment, the risk of heart failure is reduced by at least about 10%.

[0110] In one embodiment, the Pro-C3 inflammatory marker is reduced. In one embodiment, the Pro-C3 inflammatory marker is reduced to a clinically desirable level.

[0111] In one embodiment, CRP levels are reduced. In one embodiment, CRP levels are reduced to clinically desirable levels.

[0112] In one embodiment, the risk of a composite of the following outcomes is reduced: hospitalization for HFpEF or death.

[0113] In one embodiment, the risk of death or hospitalization due to HFpEF is reduced in patients treated with an effective amount of telpotide or a pharmaceutically acceptable salt thereof.

[0114] In one embodiment, the risk of a composite of the following outcomes is reduced: HFpEF or cognitive decline.

[0115] In one embodiment, the risk of a composite of the following outcomes is reduced: cognitive decline, HFpEF, or HFrEF.

[0116] In one embodiment, the risk of a composite of the following outcomes is reduced: cognitive decline, HFpEF, or death.

[0117] A method for treating, preventing or delaying the development of heart failure in a patient, comprising administering a therapeutically effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week. In one embodiment, the heart failure is selected from HFpEF and HFrEF.

[0118] In one embodiment, the amount of teilpotide is selected from about 5.0 mg, about 10.0 mg, and about 15.0 mg.

[0119] In one embodiment, the amount of teilpotide is about 5.0 mg.

[0120] In one embodiment, the amount of telpotide is about 10.0 mg.

[0121] In one embodiment, the amount of teilpotide is about 15.0 mg.

[0122] In one embodiment, the patient is at least 50 years old. In one embodiment, the patient is at least 65 years old.

[0123] In one embodiment, the weekly administration of telportide continues for at least 2 years.

[0124] In one embodiment, the weekly administration of telpotide continues for at least 3 years.

[0125] In one embodiment, the weekly administration of telpotide continues for at least 4 years.

[0126] In one embodiment, the weekly administration of telportide continues for about 5 years.

[0127] In one embodiment, the weekly administration of teilpotide continues for at least 5.5 years.

[0128] In one embodiment, telpotide or a pharmaceutically acceptable salt thereof is administered using a dose escalation regimen.

[0129] In one embodiment, the patient is also administered standard of care for reducing the risk of major adverse cardiovascular events.

[0130] In one embodiment, the patient is also administered standard of care for treating symptoms of comorbid conditions of HFrEF.

[0131] In one embodiment, the patient is also administered a maximum tolerated dose of an ACE inhibitor.

[0132] In one embodiment, the patient is also administered the maximum tolerated dose of an ARB.

[0133] In one embodiment, the patient is also administered a beta-blocker.

[0134] In one embodiment, a calcium channel blocker is also administered to the patient.

[0135] In one embodiment, a diuretic is also administered to the patient.

[0136] In one embodiment, an antithrombotic agent is also administered to the patient.

[0137] In one embodiment, aspirin is also administered to the patient.

[0138] In one embodiment, the patient is also administered a statin.

[0139] Tipoleptide or a pharmaceutically acceptable salt thereof, for use in any of the above embodiments.

[0140] Use of telpotide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in any of the above embodiments.

[0141] Further embodiments are described in the following examples, which should not be considered limiting. Example

[0142] The inclusion criteria listed in Table 1 below were designed to include participants similar to patients seen in a typical diabetes practice with varying cardiovascular risk factors or established cardiovascular disease:

[0143] Key inclusion criteria T2DM with HbA1c ≤9.5% Stable doses of 0, 1, or 2 oral glucose-lowering drugs + basal insulin for ≥ 3 months <![CDATA[BMI ≥ 23 kg / m 2 ]]> If age ≥50 years, at least one of the following: history of myocardial infarction; history of ischemic stroke; coronary revascularization ≥ 2 years ago; carotid or peripheral revascularization ≥ 2 months ago; hospitalization for unstable angina; imaging-confirmed myocardial ischemia; or percutaneous coronary intervention If age ≥55 years, any of the above or at least one of the following: documented myocardial ischemia by stress testing or imaging; >50% coronary, carotid, or lower extremity artery stenosis; ankle-brachial index <0.9; eGFR persistently <60 mL / min / 1.73 m2; hypertension with left ventricular hypertrophy; or persistent proteinuria If age ≥60 years, any of the above or at least two of the following: any tobacco use; use of lipid-lowering therapy in the past 6 months or documented untreated LD cholesterol ≥3.4 mmol / L (130 mg / dL); HDL cholesterol <1.0 mmol / L (40 mg / dL) for men and <1.3 mmol / L (50 mg / dL) for women or triglycerides ≥2.3 mmol / L (200 mg / dL) in the past 6 months; use of ≥1 blood pressure medication or untreated systolic BP ≥140 mm Hg or diastolic BP ≥95 mm Hg; or waist-to-hip ratio >1.0 (for men) and >0.8 (for women) Run-in adherence = 100% Sign the informed consent form

[0144] Table 1. Inclusion criteria.

[0145] The study was designed to consist of a screening visit followed by a single-blind 3-week placebo run-in period. Thereafter, patients were randomized to tepol 5, 10, or 15 mg (administered using an ascending dose schedule) or placebo and followed up at approximately 6-month intervals. Patients were followed until approximately 1,200 patients experienced a primary endpoint event, adjudicated assuch.

[0146] The analysis included an assessment of the effect of tepol on cognitive decline as measured by 2 different cognitive tests - the MOCA and the DSST - administered at baseline and at the 2-year, 5-year, and end-of-study visits. The MOCA and DSST methods are described in more detail above.

[0147] The primary cognitive outcome was nationally standardized substantial cognitive decline (SCD), which was defined as a decrease in MOCA or DSST scores of ≥ 1.5 standard deviations from an individual's baseline score. National standardization was achieved by first calculating the baseline mean and standard deviation of MOCA and DSST scores within each country. These baseline means and standard deviations were used to calculate 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 individual's score at that time point and dividing the difference by the country-specific baseline standard deviation. Additional cognitive outcomes included SCD and a composite of death, stroke, stroke or TIA, and stroke, TIA, or death, as well as changes in standardized MOCA and DSST scores over time.

[0148] Cognitive analyses were restricted to participants with a baseline MOCA or DSST score and at least 1 follow-up score of the same type.

[0149] Continuous variables were summarized using mean and standard deviation, and binary variables were summarized using counts and percentages. Cox proportional hazards models were used to estimate the risk of death from tebuconazole before and after treatment with tebuconazole considering each individual's baseline standardized MOCA and DSST scores. vs Hazards of SCD and the composite outcome based on placebo. The sensitivity of the Cox model to the discrete nature of the outcome due to intermittent administration of cognitive testing was assessed by repeating the primary analysis using a discrete time-proportional odds logistic model. Where 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, repeated measures linear mixed-effects models estimated the effects of tepoxetine on standardized MOCA and DSST scores with the least mean squared error, using standardized baseline scores as covariates, participant as a random effect, and treatment, visit, and treatment-visit interaction as fixed effects. See Senn S. Change from baseline and analysis of covariance revisited. Stat Med2006;25(24):4334-44.

[0150] Statistical analysis was performed using SAS software.

[0151] Example 2

[0152] A 52-week Phase 3 maximally tolerated dose (up to 15 mg / week) 6-minute walk test ("6MWT") study was conducted in obese and HFpEF patients. A sample size of 500 patients was randomized 1:1 to placebo and telportide (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 relevant magnetic resonance imaging ("MRI") measures, including, e.g., left ventricular ("LV") strain, LV mass index.

[0153] Example 3

[0154] In the Phase 2 study (GPGB), patients receiving 15 mg / week of telpotide demonstrated improvements in C-reactive protein ("CRP"), vascular cell adhesion molecule 1 ("VCAM-1"), and intercellular adhesion molecule-1 ("ICAM-1"). Improvements in the plasma collagen type III ("Pro-C3") biomarker were observed in both the 10 mg / week and 15 mg / week patient groups.

[0155] sequence

[0156] SEQ ID NO:1

[0157] Telportide

[0158] YX 1 EGTFTSDYSIX 2 LDKIAQKAFVQWLIAGGPSSGAPPPS

[0159] Where X 1 It's Aib;X 2 is Aib; the K at position 20 is obtained by replacing (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu) 1 -CO-(CH 2 ) 18 -CO 2 H was chemically modified by being conjugated to the ε-amino group of the K side chain; and the C-terminal amino acid was amidated to form a C-terminal primary amide. Sequence Listing <110> Eli Lilly and Company <120> Therapeutic uses of telpotide <130> X22678 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic constructs <220> <221> MISC_FEATURE <222> (2) <223> Xaa at position 2 is the non-naturally occurring amino acid 2-aminoisobutyric acid <220> <221> MISC_FEATURE <222> (13) <223> Xaa at position 13 is the non-naturally occurring amino acid 2-aminoisobutyric acid <220> <221> MOD_RES <222> (20)..(20) <223> Lys at position 20 was chemically modified by conjugation to the ε-amino group of the K side chain with (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2)18-CO2H <220> <221> MOD_RES <222> (39)..(39) <223> Ser at position 39 is amidated to a C-terminal primary amide <400> 1 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Xaa Leu Asp Lys 1 5 10 15 Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser 35

Claims

1. Use of telpotide or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is used for a method for treating, preventing or delaying the development of HFpEF in a patient, the method comprising administering an effective amount of telpotide or a pharmaceutically acceptable salt thereof to the patient once a week.

2. The use according to claim 1, wherein the patient has type 2 diabetes.

3. The use according to claim 1, wherein the patient is obese.

4. The use according to claim 1, wherein the patient is not obese.

5. Use of telpotide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a method for improving weight management and preventing or delaying HFpEF in patients with type 2 diabetes, the method comprising administering an effective amount of telpotide 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 hospitalization due to HFpEF.

7. The use according to any one of claims 1 to 5, wherein the method comprises administering to a patient once a week an effective amount of telpotide or a pharmaceutically acceptable salt thereof, wherein the method results in a reduced risk of death from HFpEF.

8. The use according to any one of claims 1 to 5, wherein the patient's 6-minute walk test improves by about 10%.

9. The use according to any one of claims 1 to 5, wherein the patient's risk of a composite of the following outcomes is reduced: cognitive decline, hospitalization due to HFpEF, or death.

10. The use according to any one of claims 1 to 5, wherein the therapeutically effective amount of teilpotide is selected from about 5.0 mg, about 10.0 mg and about 15.0 mg.

11. The use of claim 10, wherein the therapeutically effective amount of teilpotide is about 15.0 mg.

12. The use according to any one of claims 1 to 5, wherein the weekly administration of teilpotide is continued for at least 2 years.

13. The use according to any one of claims 1 to 5, wherein the patient has: multiple cardiovascular risk factors without confirmed cardiovascular disease; or confirmed cardiovascular disease.