The present invention relates to the field of medicine. Provided are methods
relating to treating, preventing, or delaying disorders relating to cognition, such as
5 cognitive decline, cognitive impairment or dementia. Provided are methods relating to
treating, preventing, or delaying heart failure.
Patients with type 2 diabetes mellitis (T2DM) frequently suffer from a variety of
comorbidities, including cognitive issues such as cognitive decline, cognitive impainnent
or dementia. People with diabetes are 1.5 to 2 times more likely than unaffected people
10 to experience cognitive decline, minimal cognitive impairment or dementia. This
relationship is independent of other risk factors for cognitive dysfunction and accounts for
a prevalence of 13% in people with diabetes aged 65-74 years and 24% in people aged 75
years or older. No single cause has been identified for the high risk of cognitive
dysfunction in people with diabetes. The possibility that certain diabetes treatments,
15 including glucagon-like peptide-I (GLP-1) receptor agonists, may have benefits on
cognitive function has been proposed and is being studied. See, e.g., GD Femminella, et
al., Evaluating the effects ~[the novel GLP-1 analogue liraglutide in Alzheimer's disease:
study protocol for a randomized controlled trial (ELAD study), 20 TRIALS 191 (2019).
There remains a need, however, for therapies to treat, prevent or delay cognitive decline,
20 cognitive impairment or dementia, including in patients with T2DM.
Patients with type 2 diabetes mellitis (T2DM) are at risk for 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
25 lifestyle modification to induce weight loss and administration of agents for symptom
relief of co-morbid conditions. Bariatric surgery showed some benefit in patients with
HFpEF. See, e.g., Mikhalkova, et al., Obesity (2018). Despite the increasing incidence
ofHFpEF, effective treatment options have been largely unsuccessful. See, e.g., Zheng
et.al, Drug treatment effects on outcomes in heart failure with preserved ejection
30 fraction: a systematic review and meta-analysis, Heart. 104 (5): 407--415 (March 2018).
There is currently no approved pharmaceutical treatment for HFpEF. There is a need for
3
therapies to treat, prevent or delay HFpEF. There is a need for therapies to treat, prevent,
or delay HFrEF.
The present invention provides methods for treating, preventing or delaying
cognitive disorders, such as cognitive decline, cognitive impairment or dementia.
5 Accordingly, the present invention provides a method of treating, preventing or
delaying development of a cognitive disorder in a patient, comprising administering
tirzepatide in a therapeutically effective amount to the patient once weekly.
In another aspect, the present invention provides a method of preventing or
delaying cognitive decline in a patient, comprising administering tirzepatide in a
10 therapeutically effective amount to the patient once weekly.
15
In another aspect, the present invention provides a method of improving glycemic
control and treating, preventing or delaying cognitive decline in a patient in a patient with
type 2 diabetes mellitus, comprising administering tirzepatide in a therapeutically
effective amount to the patient once weekly.
In another aspect, the present invention provides a method of improving glycemic
control in a patient with type 2 diabetes mellitus and at risk for cognitive decline,
comprising administering tirzepatide in a therapeutically effective amount to the patient
once weekly, wherein the method provides a reduction in the risk of the patient
experiencing cognitive decline.
20 In another aspect, the present invention provides tirzepatide for use in treating,
preventing or delaying development of a cognitive disorder in a patient, comprising
administering tirzepatide in a therapeutically effective amount to the patient once weekly.
In another aspect, the present invention provides use of tirzepatide for the
preparation of a medicament for treating, preventing or delaying development of a
25 cognitive disorder in a patient, comprising administering tirzepatide in a therapeutically
effective amount to the patient once weekly.
The present invention provides methods for treating, preventing or delaying heart
failure, comprising administering an effective amount oftirzepatide, or a
pharmaceutically acceptable salt thereof to a patient in need of such treatment.
30 Accordingly, the present invention provides a method of treating, preventing or
delaying development of a HFpEF in a patient, comprising administering an effective
4
amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to the patient once
weekly.
Accordingly, the present invention provides a method of treating, preventing or
delaying development of a HFrEF in a patient, comprising administering an effective
5 amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to the patient once
weekly.
10
In another aspect, the present invention provides a method of preventing or
delaying HFpEF in a patient, comprising administering an effective amount oftirzepatide,
or a pharmaceutically acceptable salt thereof, to the patient once weekly.
In another aspect, the present invention provides a method of preventing or
delaying HFrEF in a patient, comprising administering an effective amount of tirzepatide,
or a pham1aceutically acceptable salt thereot~ to the patient once weekly.
In another aspect, the present invention provides a method of improving glycemic
control and treating, preventing or delaying HFpEF in a patient in a patient with type 2
15 diabetes mellitus, comprising administering an effective amount of tirzepatide, or a
pharmaceutically acceptable salt thereo( to the patient once weekly.
In another aspect, the present invention provides a method of improving glycemic
control and treating, preventing or delaying HFrEF in a patient in a patient with type 2
diabetes mellitus, comprising administering an effective amount of tirzepatide, or a
20 pharmaceutically acceptable salt thereof, to the patient once weekly.
In another aspect, the present invention provides a method of improving glycemic
control in a patient with type 2 diabetes mellitus and at risk for HFpEF, comprising
administering an effective amount oftirzepatide, or a pharmaceutically acceptable salt
thereof, to the patient once weekly, wherein the method provides a reduction in the risk of
25 the patient experiencing HFpEF.
In another aspect, the present invention provides a method of improving glycemic
control in a patient with type 2 diabetes mellitus and at risk for HFrEF, comprising
administering an effective amount of tirzepatide, or a pharmaceutically acceptable salt
thereof, to the patient once weekly, wherein the method provides a reduction in the risk of
30 the patient experiencing HFrEF.
In another aspect, the present invention provides a method of improving weight
management in a patient with obesity and at risk for HFpEF, comprising administering an
5
effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to the
patient once weekly, wherein the method provides a reduction in the risk of the patient
experiencing HFpEF.
In another aspect, the present invention provides a method for treating HFpEF in
5 patient at risk for HFpEF, comprising administering an effective amount oftirzepatide, or
a phannaceutically acceptable salt thereof, to the patient once weekly, wherein the
patient's weight is within a normal weight range for the patient.
In another aspect, the present invention provides a method of improving weight
management in a patient with obesity and at risk for HFrEF, comprising administering an
10 effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to the
patient once weekly, wherein the method provides a reduction in the risk of the patient
experiencing HFrEF.
In another aspect, the present invention provides tirzepatide, or a pharmaceutically
acceptable salt thereo( for use in treating, preventing or delaying development ofHFpEF
15 in a patient, comprising administering an effective amount of tirzepatide to the patient
once weekly.
In another aspect, the present invention provides tirzepatide, or a pharmaceutically
acceptable salt thereof, for use in treating, preventing or delaying development ofHFrEF
in a patient, comprising administering an effective amount of tirzepatide to the patient
20 once weekly.
25
In another aspect, the present invention provides use of tirzepatide, or a
pharmaceutically acceptable salt thereof: for the preparation of a medicament for treating,
preventing or delaying development ofHFpEF in a patient, comprising administering
tirzepatide in a therapeutically effective amount to the patient once weekly.
In another aspect, the present invention provides use of tirzepatide for the
preparation of a medicament for treating, preventing or delaying development ofHFrEF
in a patient, comprising administering tirzepatide, or a pharmaceutically acceptable salt
thereof, in a therapeutically effective amount to the patient once weekly.
US9474780 describes and claims tirzepatide. When used herein, the term
30 "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 seeking approval of a GIP/GLP-1 receptor agonist product which relies in
6
whole or part upon data submitted to a regulatory agency by Eli Lilly and Company
relating to tirzepatide, regardless of whether the party seeking approval of said protein
actually identifies the protein as tirzepatide or uses some other term. Tirzepatide agonizes
the GIP/GLP-1 receptors resulting in stimulation of insulin synthesis and secretion, and
5 has been shown to provide improved glycemic control in T2DM patients.
10
Cognitive Decline.
The development or progression of cognitive decline may be reflected in scores
generated through administration of measures of cognitive status, such as the Montreal
Cognitive Assessment (MoCA) and the Digit Symbol Substitution Test (DSST).
The MOCA is a cognitive screening test that has been validated in the setting of
mild cognitive impairment and subsequently adopted in numerous clinical settings. The
test comprises a 1-page 30-item questionnaire 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 abilities,
15 executive function, attention, concentration, working memory and language. See, e.g.,
Nasreddine ZS, et al. The Montreal Cognitive Assessment, MaCA: 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:
20 a population-based study. STROKE 2010; 41(6): 1290-3. The MOCA score is equal to the
number of items out of 30 answered correctly, plus 1 extra point if the individual reports
:S 12 years of education. Controlled 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 report much lower mean
25 scores. See, e.g., Rossetti HC, et al., Normative data for the Montreal Cognitive
Assessment (MaCA) in a population-based sample. NEUROLOGY 2011; 77(13): 1272-5.
The DSST is a subtest of the Wechsler Adult Intelligence Scale (3rd Edition) and
assesses a wide array of cognitive domains including visual-motor speed and
coordination, capacity for learning, attention, concentration and short-term memory. See
30 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 of9 randomly ordered symbols with a blank square
7
underneath, and a key at the top of the page that pairs each symbol to a number.
Respondents fill the blank space under each symbol with the corresponding number as
quickly as possible over a 2-minute period. The score is the number of consecutive digitsymbol
pairs correctly completed within 2 minutes, and the maximum possible score is
5 135. It has been extensively used to measure cognitive function in cognitively intact
individuals with and without diabetes, and validation studies have demonstrated that it
predicts future cognitive dysfunction and disability; is relatively easy to administer; is not
language specific; and its score is correlated with measures of physical function and
future cognitive decline. See, e.g., Rosano C, et al., Association Between Lower Digit
10 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 middleaged
adults. NEUROLOGY. 56(1):42-8 (2001). When the DSST was used in randomized
controlled trials involving cognitively intact people with dysglycemia, mean baseline
15 scores ranged 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 (ACCORD
20 MIND): a randomised open-label substudy. LANCETNEUROL. (2011); 10(11): 969-77.
Previous studies have suggested that the normal range of cognitive tests scores
may differ by country. Rossetti HC, et al., Normative data for the Montreal Cognitive
Assessment (MaCA) in a population-based sample. NEUROLOGY 2011; 77(13): 1272-5;
Thomann AE, et al. The Montreal Cognitive Assessment: Normative Data from a
25 German-Speaking Cohort and Comparison with International Normative Samples. J.
ALZHEIMER's DIS. 2018; 64(2): 643-55. Thus, when assessing substantive decline in
populations that include individuals from multiple countries, it may be desirable to
standardize each individual's score at each time-point to a mean baseline score and
standard deviation of the values achieved within his or her country, as opposed to the
30 mean and standard deviation of the entire population.
Previous studies have also noted that cognitive test scores decline very slowly
with time in groups of middle-aged individuals, but that some individuals experience
8
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
5 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 decline by 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
10 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.
When used herein, the term "cognitive disorder" refers to any condition
15 involving impairments in a person's cognitive function, such as difficulties with memory,
learning new things, ability to concentrate and/or decision-making that affects the
person's everyday life. Such impairment ranges 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
20 may be characterized by a slight but noticeable and measurable decline in cognitive
abilities, including memory and thinking skills, but without loss in ability to undertake
everyday activities. More severe impairment, or dementia, is associated with losses in
ability to perform everyday activities, and depending on the severity, the abilities to read,
write, and/or understand meaning or significance of things.
25 The methods provided herein may be most effective in patients at relatively higher
risk for experiencing cognitive decline. In certain embodiments, such patients are those
having one or more of: T2DM; hypertension; elevated cholesterol and/or obesity.
In certain embodiments, such patients have established cardiovascular disease;
and/or one or more risk factors for major adverse cardiovascular events.
30 Heart Failure.
Heart failure with preserved t:iection fraction (HFpEF) is a form of heart failure in
which the .s-j_~_~_tj_g_gJ:nt~~lj_Q.r!- the percentage of the volurne ofblood ejected from the left
9
ventricle with each heartbeat divided by the volume of blood when the left ventricle is
maxirnally filled- is normal, defined as greater than 50~o. Despite an increased incidence
ofHFpEF, efforts to eiTectively treat HFpEF have been largely unsuccessful.
Conventionally, heart failure has been treated with a variety of drugs to treat the
5 comorbid symptoms. Such treatments include alpha-adrenergic agonists, beta-adrenergic
agonists, calcium channel antagonists, cardiac glycosides, diuretics, nitrates,
phosphodiesterase inhibitors, prazosin, and a variety ofvasodilators. These treatments
are associated with undesired side effects. For example, alpha-adrenergic agonists may
be associated with edema of the peripheral tissues. Certain treatments are associated with
10 desensitization to the drug, rendering the treatment ineffective. There is a continued
demand for a treatrnent for HFpEF with an acceptable phannaceutical side effect proti.le.
Further, the is a demand for a treatment for HFrEF with an acceptable pharmaceutical
side effect profile.
When used herein, the term "substantive cognitive decline" or "SCD" refers to a
15 significant decrease in a subject's score in a standardized cognitive assessment, such as
MoCA or DSST of 1.5 standard deviations or greater.
When used herein, the terms "country-standardization," "country-standardized,"
and the like, refer to normalization of cognitive function scores by: calculating the
baseline mean and standard deviation of the scores within each country; and using these
20 baseline mean and standard deviations to calculate a standardized MOCA and DSST
score for each participant at each time point by subtracting the country-specific baseline
mean score from each individual's score at that time point and dividing the difference by
the country-specific baseline standard deviation.
When used herein, the term "major adverse cardiovascular events" refers to
25 cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. These events
are also sometimes referred to as MACE or MACE 3 events. The first to occur of any of
these events is a composite endpoint frequently used in CVOTs.
When used herein in relation to major adverse cardiovascular events, the term
"risk factors" refers to characteristics of T2DM patients understood to increase their risk
30 for a major adverse cardiovascular event. Such risk factors include in particular any of
the following: current tobacco use (any form of tobacco); use of at least 1 approved lipid
modifying therapy (e.g., statins such as atorvastatin, rosuvastatin, simvastatin, pravastatin,
10
lovastatin, fluvastatin or pitavastatin; PCSK9 inhibitors, such as evolocumab or
alirocumab; and ezetimibe) to treat hypercholesterolemia or a documented untreated lowdensity
lipoprotein cholesterol (LDL-C) 2:3.4 mmol/L (130 mg/dL) within the past 6
months; documented treated or untreated high-density lipoprotein cholesterol (HDL-C)
5 <1.0 mmol/L (40 mg/dL) for men and <1.3 mmol/L (50 mg/dL) for women or
triglycerides 2:2.3 mmol/L (200 mg/dL) within the past 6 months; use of at least 1 blood
pressure medication to treat hypertension (e.g., angiotensin converting enzyme (ACE)
inhibitors, angiotensin receptor blockers (ARBs), thiazidelike diuretics, and
dihydropyridine calcium channel blockers) or untreated systolic blood pressure (SBP)
10 2:140 mm Hg or diastolic blood pressure (DBP) 2:95 mmHg; measured waist-to-hip ratio
> 1. 0 for men and >0. 8 for women.
As used herein "improved weight management" means that the patient weight is
within or closer to the clinically defined normal weight range for the patient. "Normal
weight" for a particular patient may be determined by a clinician considering applicable
15 considerations that are well known to the skilled clinician. Typically, improved weight
management means that the patient loses weight to reach a weight that is within, or closer
to, the desired weight range for the patient. As used herein "normal weight range" shall
be a weight that a skilled clinician determines to be the normal weight for a particular
patient. The normal weight range may vary based on the height of the patient and other
20 factors considered by the skilled clinician in weight assessment.
When used herein, the terms "treatment," ''treat," "treating," and the like, are
meant 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
25 condition is not actually eliminated and even if progression of the disorder or condition is
not itself slowed or reversed. \Vhen used herein, the terms "prevent," "preventing,"
"prevention," and the like, are meant to indude avoidance of the onset of a disease,
condition, disorder or symptom. When used herein, the terms ''delay," "delaying," and
the like, are meant to include increasing the duration of time that occurs until onset of a
30 disease, condition, disorder or symptom.
When used herein in connection with multiple outcomes, the term "composite"
refers to the first to occur of any of the outcomes.
11
When used herein, the tem1 "hazard ratio" refers to a measure of the relative rate
of progression to an endpoint as corn pared to a control group. In outcome-based clinical
trials, a reduction in the hazard ratio for a test am1 as compared to the control indicates
the therapy used in the test arm reduces the risk of the endpoint, in the case of the studies
5 described herein, major adverse cardiovascular events.
"Therapeutically effective amount" means the amount of tirzepatide for the
methods and uses of the present in'vention or pharmaceutical composition comprising
tirzepatide for the methods and uses of the present invention that will elicit the biological
or medical response of or desired therapeutic effect on the patient that is being sought by
10 the researcher, medical doctor, or other clinician. An effective amount oftirzepatide may
vary according to factors such as the disease state, age, sex, and weight of the individual,
and the ability oftirzepatide to elicit a desired response in the individual. An effective
amount is also one in which any toxic or detrimental effect is outweighed by the
therapeutically beneficial effects. In certain embodiments, the therapeutically effective
15 amount oftirzepatide for use in the methods described herein is selected from the group
consisting of 5, 10 and 15 mg. In certain embodiments, the therapeutically effective
amount oftirzepatide is 5.0 mg. In certain embodiments, the therapeutically effective
amount oftirzepatide is 10.0 mg. In preferred embodiments, the therapeutically effective
amount oftirzepatide is 15.0 mg.
20 Additional embodiments of the present invention are described belm.v:
COGNITIVE DISORDER
A method of treating, preventing or delaying development of a cognitive disorder
in a patient, comprising administering tirzepatide, or a pharmaceutically acceptable salt
thereof, in a therapeutically effective amount to the patient once weekly. In an
25 embodiment, the cognitive disorder is selected from the group consisting ofMCI and
dementia.
30
A method of preventing or delaying cognitive decline in a patient, comprising
administering tirzepatide, or a pharmaceutically acceptable salt thereof, in a
therapeutically effective amount to the patient once weekly.
A method of improving glycemic control and treating, preventing or delaying
cognitive decline in a patient in a patient with type 2 diabetes mellitus, comprising
12
administering tirzepatide, or a pharmaceutically acceptable salt thereof, m a
therapeutically effective amount to the patient once weekly.
In an embodiment, the method results in a reduction in the risk of the patient
experiencing cognitive decline.
5 A method of improving glycemic control in a patient with type 2 diabetes
mellitus, comprising administering tirzepatide, or a pharmaceutically acceptable salt
thereof, in a therapeutically effective amount to the patient once weekly, wherein the
method results in a reduction in the risk of the patient experiencing cognitive decline.
The method of any of the above embodiments wherein the patient has type 2
10 diabetes mellitus.
The method of any of the above embodiments wherein the patient has one or more
of: T2DM; hypertension; elevated cholesterol and obesity.
In an embodiment, the patient has either: multiple cardiovascular risk factors
without established cardiovascular disease; or established cardiovascular disease.
15 In an embodiment, the risk factors for cardiovascular disease are selected from the
group consisting of: current tobacco use (any form of tobacco); use of at least 1 approved
lipid modifying therapy to treat hypercholesterolemia or a documented untreated lowdensity
lipoprotein cholesterol (LDL-C) 2:3.4 mmol/L (130 mg/dL) within the past 6
months; documented treated or untreated high-density lipoprotein cholesterol (HDL-C)
20 <1.0 mmol/L (40 mg/dL) for men and <1.3 mmol/L (50 mg/dL) for women or
triglycerides 2:2.3 mmol/L (200 mg/dL) within the past 6 months; use of at least 1 blood
pressure medication to treat hypertension or untreated systolic blood pressure (SBP) 2:140
mm Hg or diastolic blood pressure (DBP) 2:95 mmHg; measured waist-to-hip ratio >1.0
for men and >0.8 for women.
25 In an embodiment, the cognitive disorder is selected from the group consisting of
MCI and dementia.
In an embodiment, the patient's risk of cognitive decline is reduced by at least
about 14%.
In an embodiment, the risk of a major adverse cardiovascular event is reduced by
30 at least about 10%.
In an embodiment, the risk of a major adverse cardiovascular event is reduced by
at least about 11%.
13
5
In an embodiment, the risk of a major adverse cardiovascular event is reduced by
about 12%.
In an embodiment, the risk ofthe occurrence of a composite ofthe following
outcomes is reduced: cognitive decline or death.
In an embodiment, the risk ofthe occurrence of a composite ofthe following
outcomes is reduced: cognitive decline or stroke.
In an embodiment, the risk ofthe occurrence of a composite ofthe following
outcomes is reduced: cognitive decline, stroke or transient ischemic attack.
In an embodiment, the risk ofthe occurrence of a composite ofthe following
10 outcomes is reduced: cognitive decline, stroke, transient ischemic attack or death.
In an embodiment, the risk of cardiovascular death is lower.
In an embodiment, the risk of non-fatal stroke is lower.
In an embodiment, the risk of non-fatal myocardial infarction is lower.
In an embodiment, the risk of the occurrence of a composite of the following
15 outcomes is reduced: diabetic retinopathy needing laser, anti-VEGF therapy, or
vitrectomy; clinical proteinuria; a 30% decline in eGFR; or chronic renal replacement
therapy.
A method of treating, preventing or delaying development of a cognitive disorder
in a patient, comprising administering tirzepatide, or a pharmaceutically acceptable salt
20 thereof, in a therapeutically effective amount to the patient once weekly. In an
embodiment, the cognitive disorder is selected from the group consisting ofMCI and
dementia.
25
In an embodiment, the amount of tirzepatide is selected from the group consisting
of about 5. 0 mg, about 10.0 mg and about 15.0 mg.
In an embodiment, the amount oftirzepatide is about 5.0 mg.
In an embodiment, the amount oftirzepatide is about 10.0 mg.
In an embodiment, the amount oftirzepatide is about 15.0 mg.
In an embodiment, once weekly administration of tirzepatide, or a
pharmaceutically acceptable salt thereof, is continued for at least 2 years.
30 In an embodiment, once weekly administration oftirzepatide, or a
pharmaceutically acceptable salt thereof, is continued for at least 3 years.
14
In an embodiment, once weekly administration of tirzepatide, or a
pharmaceutically acceptable salt thereof, is continued for at least 4 years.
In an embodiment, once weekly administration of tirzepatide, or a
pharmaceutically acceptable salt thereof, is continued for approximately 5 years.
5 In an embodiment, once weekly administration of tirzepatide, or a
pharmaceutically acceptable salt thereof, is continued for at least 5.4 years.
In an embodiment, tirzepatide, or a pharmaceutically acceptable salt thereof, is
administered using a dose escalation protocol.
In an embodiment, the patient is also administered the standard of care for
10 reducing the risk of major adverse cardiovascular events.
15
20
In an embodiment, the patient is also administered the rnaximum tolerated dose of
an ACE inhibitor.
In an embodiment, the patient is also administered the maxirnurn tolerated dose of
an ARB.
In an embodiment, the patient is also administered a beta blocker.
In an embodiment, the patient is also administered a calcium channel blocker.
In an embodiment, the patient is also administered a diuretic.
In an embodiment, the patient is also administered an antithrombotic agent.
In an embodiment, the patient is also administered aspirin.
In an embodiment, the patient is also administered a statin.
Tirzepatide, or a pharmaceutically acceptable salt thereof, for use in any of the
above embodiments.
l..Jse oftirzepatide, or a pharmaceutically acceptable salt thereof, in the preparation
of a medicament for any of the above embodiments.
25 HEART FAILURE
30
A method of treating, preventing or delaying development of heart failure in a
patient, comprising administering tirzepatide, or a pharmaceutically acceptable salt
thereof, in a therapeutically effective amount to the patient once weekly. In an
embodiment, the heart failure is selected from the group consisting of HFpEF and HFrEF.
A method of preventing or delaying heart failure in a patient, comprising
administering tirzepatide, or a pharmaceutically acceptable salt thereof, in a
therapeutically effective amount to the patient once weekly.
15
5
A method of improving glycemic control and treating, preventing or delaying
heart failure in a patient in a patient with type 2 diabetes mellitus, comprising
administering tirzepatide, or a pharmaceutically acceptable salt thereof, in a
therapeutically effective amount to the patient once weekly.
In an embodiment, the method results in a reduction in the risk of the patient
experiencing HFpEF. In an embodiment, the method results in a reduction in the risk of
the patient experiencing HFrEF.
A method of improving glycemic control in a patient with type 2 diabetes
mellitus, comprising administering tirzepatide, or a pharmaceutically acceptable salt
10 thereof, in a therapeutically effective amount to the patient once weekly, wherein the
method results in a reduction in the risk of the patient experiencing cognitive decline.
The method of any of the above embodiments wherein the patient has type 2
diabetes mellitus.
The method of any of the above embodiments wherein the patient has one or more
15 of: T2DM; hypertension; elevated cholesterol and obesity.
In an embodiment, the patient has either: multiple cardiovascular risk factors
without established cardiovascular disease; or established cardiovascular disease.
In an embodiment, the risk factors for cardiovascular disease are selected from the
group consisting of: current tobacco use (any form of tobacco); use of at least 1 approved
20 lipid modifying therapy to treat hypercholesterolemia or a documented untreated lowdensity
lipoprotein cholesterol (LDL-C) 2:3.4 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) for men and <1.3 mmol/L (50 mg/dL) for women or
triglycerides 2:2.3 mmol/L (200 mg/dL) within the past 6 months; use of at least 1 blood
25 pressure medication to treat hypertension or untreated systolic blood pressure (SBP) 2:140
mm Hg or diastolic blood pressure (DBP) 2:95 mmHg; measured waist-to-hip ratio >1.0
for men and >0.8 for women.
30
In an embodiment, the heart failure is selected from the group consisting of
HFpEF and HFrEF.
In an embodiment, the patient's six minute walk test is improved. In an
embodiment the patient's six minute walk test demonstrates improved exercise capacity.
16
In an embodiment, the patient's Kansas City Cardiomyopathy Questionnaire
Clinical Summary Score (KCCQ-CSS) improves. In an embodiment, the improved
KCCQ-CSS correlates with a net clinical benefit.
In an embodiment, the patient's risk of heart failure is reduced by at least about
5 14%.
In an embodiment, the risk of heart failure is reduced by at least about 10%.
In an embodiment, Pro-C3 inflammation markers are reduced. In an embodiment,
Pro-C3 inflammation markers are reduced to a clinically desired level.
In an embodiment, the CRP levels are reduced. In an embodiment, CRP levels are
10 reduced to a clinically desired level.
In an embodiment, the risk ofthe occurrence of a composite ofthe following
outcomes is reduced: hospitalization for HFpEF or death.
In an embodiment, the risk of death or hospitalization for HFpEF is reduced in a
patient treated with an effective amount of tirzepatide, or a pharmaceutically acceptable
15 salt thereof
20
In an embodiment, the risk ofthe occurrence of a composite ofthe following
outcomes is reduced: HFpEF or cognitive decline.
In an embodiment, the risk of the occurrence of a composite of the following
outcomes is reduced: cognitive decline, HFpEF or HFrEF.
In an embodiment, the risk ofthe occurrence of a composite ofthe following
outcomes is reduced: cognitive decline, HFpEF, or death.
A method of treating, preventing or delaying development of a heart failure in a
patient, comprising administering tirzepatide, or a pharmaceutically acceptable salt
thereof, in a therapeutically effective amount to the patient once weekly. In an
25 embodiment, the heart failure is selected from the group consisting of HFpEF and HFrEF.
30
In an embodiment, the amount of tirzepatide is selected from the group consisting
of about 5.0 mg, about 10.0 mg and about 15.0 mg.
In an embodiment, the amount oftirzepatide is about 5.0 mg.
In an embodiment, the amount oftirzepatide is about 10.0 mg.
In an embodiment, the amount oftirzepatide is about 15.0 mg.
In an embodiment, the patient is at least 50 years old. In an embodiment, the
patient is at least 65 years old.
17
In an embodiment, once weekly administration of tirzepatide is continued for at
least 2 years.
In an embodiment, once weekly administration of tirzepatide is continued for at
least 3 years.
5 In an embodiment, once weekly administration of tirzepatide is continued for at
least 4 years.
In an embodiment, once weekly administration of tirzepatide is continued for
approximately 5 years.
In an embodiment, once weekly administration of tirzepatide is continued for at
10 least 5.5 years.
In an embodiment, tirzepatide, or a pharmaceutically acceptable salt thereof, is
administered using a dose escalation protocol.
In an embodiment, the patient is also administered the standard of care for
reducing the risk of major adverse cardicrvascular events.
15 In an embodiment, the patient is also administered the standard of care for treating
the symptoms of conditions comorbid with 1--l:FrEF.
In an embodiment, the patient is also administered the maximum tolerated dose of
an ACE inhibitor.
In an embodiment, the patient is also administered the maximum tolerated dose of
20 an ARB.
25
In an embodiment, the patient is also administered a beta blocker.
In an embodiment, the patient is also administered a calcium channel blocker.
In an embodiment, the patient is also administered a diuretic.
In an embodiment, the patient is also administered an antithrombotic agent.
In an embodiment, the patient is also administered aspirin.
In an embodiment, the patient is also administered a statin.
Tirzepatide, or a pharmaceutically acceptable salt thereat~ for use in any of the
above embodiments.
Use of tirzepatide, or a phannaceutically acceptable salt thereof: in the preparation
30 of a medicament for any ofthe above embodiments.
Further embodiments are described in the examples below, which are not to be
construed as limiting.
18
EXAl\'U)LES
The enrollment criteria, set forth in Table 1 below, are designed to include
participants who are similar to patients seen within a typical diabetes practice, who have
varying cardiovascular risk factors or established cardiovascular disease:
Key inclusion criteria
T2DM with HbA1c :S9.5%
Stable dose of 0, 1 or 2 oral glucose-lowering drugs± basal insulin for 2:3 months
BMI 2: 23 kg/m 2
If age 2:50 years, at least 1 of: prior MI; prior ischaemic stroke; coronary
revascularization 2:2 years earlier; carotid or peripheral revascularization 2:2 months
earlier; unstable angina hospitalization; image proven myocardial ischaemia; or
percutaneous coronary intervention
If age 2:55 years, any of the above or at least 1 of: documented myocardial ischaemia
by stress test 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 albuminuria
If age 2: 60 years, any of the above or at least 2 of: any tobacco use; use of lipidmodifying
therapy or a documented untreated LDL cholesterol2:3.4 mmol/L (130
mg/dL) within the past 6 months; HDL cholesterol <1.0 mmol/L (40 mg/dL) for men
and <1.3 mmol/L (50 mg/dL) for women or triglycerides 2:2.3 mmol/L (200 mg/dL)
within the past 6 months; use of2:1 blood pressure drug or untreated systolic blood
pressure 2: 140 mm Hg or diastolic blood pressure 2: 95 mm Hg; or waist-to-hip ratio
>1.0 (men) and >0.8 (women)
Run-in adherence to study drug= 100%
Signed informed consent
5 Table 1. Enrollment Criteria.
The study is designed to consist of a screening visit followed by a single-blind 3-
week placebo run-in period. Afterwards, patients are randomized to either tirzepatide 5,
10, or 15 mg (dosed using an escalation dose protocol) or placebo and followed at
approximately 6-month intervals. Patients are followed until approximately 1200 patients
10 experience a primary endpoint event, adjudicated as such.
19
Analyses include assessment of the effects of tirzepatide on cognitive decline, as
measured through administration of 2 different cognitive instruments- MOCA and DSST
-at baseline and at the 2-year, 5-year and end-of-study visits. The MOCA and DSST
5 methods are described in more detail above.
The primary cognitive outcome is country-standardized substantive cognitive
decline (SCD), which is defined as a reduction of either the MOCA or DSST score of2:
1.5 standard deviations from the individual's baseline score. Country-standardization is
accomplished by first calculating the baseline mean and standard deviation of the MOCA
10 and DSST score within each country. These baseline mean and standard deviations are
used to calculate a standardized MOCA and DSST score for each participant at each time
point. This is 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 include composites of SCD
15 with death, stroke, stroke or TIA, and stroke, TIA or death, and the change in
standardized MOCA and DSST scores over time.
Cognitive analyses are restricted to participants who have a baseline MOCA or
DSST score and at least 1 follow-up score of the same type.
Continuous variables are summarized using means with standard deviations and
20 binary variables are summarized using counts with percentages. Cox proportional hazard
models are used to estimate the hazard of SCD and SCD-based composite outcomes with
tirzepatide versus placebo, both before and after accounting for each individual's baseline
standardized MOCA and DSST scores. Sensitivity of the Cox model to the discrete nature
of the results due to the intermittent administration of the cognitive tests is assessed by
25 repeating the main analyses using a discrete time proportional odds logistic model. Where
indicated, Cox models account 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 for effects within
subgroups are explored by including the subgroup, and a subgroup-treatment interaction
30 term in the model. Finally, repeated measures linear mixed-effects models estimate the
effect of tirzepatide on the least square mean difference in the standardized MOCA and
DSST scores, with the standardized baseline scores as covariates, participant as a random
20
5
effect, and fixed effects for treatment, visit, and treatment-visit interaction. See Senn S.
Change from baseline and analysis of covariance revisited. Stat Med 2006; 25(24): 4334-
44.
Statistical analyses are completed using SAS software.
EXAMPLE2
A 52-week Phase 3 maximum tolerated dose, up to 15 mg/week, six-minute walk
test ("6MWT") study in patients with obesity and HFpEF is conducted. A sample size of
500 patients are randomized 1:1 with placebo and tirzepatide (maximum tolerated dose up
to 15 mg/week). The study will measure the 6MWT, weight loss, Kansas City
10 Cardiomyopathy Questionnaire ("KCCQ"), Churg-Strauss Syndrome ("CSS"), left atrial
15
20
volume index ("LA VI"), ectopic atrial tachycardia ("EAT"), and magnetic resonance
imaging ("MRI") measures of interest, including, for example, left ventricle ("LV")
strain, LV mass index.
Example 3
In a Phase 2 study (GPGB), tirzepatide patients receiving 15 mg/week tirzepatide
show improvement inC-Reactive Protein ("CRP"), vascular cell adhesion molecule 1
("VCAM-1"), and intercellular adhesion molecule-I ("ICAM-1"). Plasma collagen type
III ("Pro-C3") biomarker improvement is observed in the lOmg/week and 15 mg/week
patient groups.
21
Sequences
SEQ ID NO: I
Tirzepatide
YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS
5 wherein X1 is Aib; X2 is Aib; Kat position 20 is chemically modified through
conjugation to the epsilon-amino group of the K side-chain with (2-[2-(2-Amino-ethoxy)ethoxy
]-acetyl)2-(yGlu)1-CO-(CH2)1s-C02H; and the C-terminal amino acid is amidated
as a C-terminal primary amide.
22
WE CLAIM:
1. A method of treating, preventing or delaying development of a cognitive
disorder in a patient, comprising administering an effective amount of tirzepatide, or a
5 pharmaceutically acceptable salt thereof, to the patient once weekly.
2. The method as claimed by claim 1, wherein the cognitive disorder is
selected from the group consisting ofMCI and dementia.
3. A method of preventing or delaying cognitive decline in a patient,
comprising administering an effective amount oftirzepatide, or a pharmaceutically
10 acceptable salt thereof, to the patient once weekly.
4. The method as claimed by any one of Claims 1 to 3 wherein the patient
has type 2 diabetes mellitus.
5. A method of improving glycemic control and preventing or delaying
cognitive decline in a patient in a patient with type 2 diabetes mellitus, comprising
15 administering an effective amount of tirzepatide or a pharmaceutically acceptable salt
thereof, to the patient once weekly.
6. The method as claimed by any one of claims 1 to 5, wherein the method
results in a reduction in the risk of the patient experiencing cognitive decline.
7. A method of improving glycemic control in a patient with type 2 diabetes
20 mellitus, comprising administering an effective amount of tirzepatide or a
pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method
results in a reduction in the risk of the patient experiencing cognitive decline.
8. The method as claimed by any one of claims 1 to 7 wherein the patient's
risk of cognitive decline is reduced by about 14%.
25 9. The method as claimed by any one of claims 1 to 8, wherein the patient's
risk of the occurrence of a composite of the following outcomes is reduced: cognitive
decline, stroke, transient ischemic attack or death.
10. The method as claimed by any one of claims 1 to 9 wherein the
therapeutically effective amount oftirzepatide is selected from the group consisting of
30 about 5.0 mg, about 10.0 mg and about 15.0 mg.
11. The method as claimed by claim 10 wherein the therapeutically effective
amount oftirzepatide is about 15.0 mg.
23
12. The method as claimed by any of claims 1 to 11 wherein once weekly
administration of tirzepatide is continued for at least 2 years.
13. The method as claimed by any one of claims 1 to 12 wherein the patient
has either: multiple cardiovascular risk factors without established cardiovascular disease;
5 or established cardiovascular disease.
14. A method of treating, preventing or delaying development of heart failure
in a patient, comprising administering an effective amount of tirzepatide, or a
pharmaceutically acceptable salt thereof, to the patient once weekly.
15. The method of claim 14, wherein the heart failure is selected from the
10 group consisting ofHFrEF and HFpEF.
16. The method of Claim 15 wherein the heart failure is HFpEF.
17. A method of preventing or delaying HFpEF in a patient, comprising
administering an effective amount of tirzepatide, or a pharmaceutically acceptable salt
thereof, to the patient once weekly.
15 18. The method as claimed by any one of Claims 14 to 17 wherein the patient
has type 2 diabetes mellitus.
19. The method as claimed by any one of Claims 14 to 18 wherein the
patient's weight is obese.
20. The method as claimed by any one of Claims 14 to 18 wherein the
20 patient's weight is not obese.
21. A method of improving weight management and preventing or delaying
HFpEF in a patient in a patient with type 2 diabetes mellitus, comprising administering an
effective amount oftirzepatide or a pharmaceutically acceptable salt thereof, to the
patient once weekly.
25 22. The method as claimed by any one of claims 14 to 21, wherein the method
provides a reduced risk of hospitalization for HFpEF ..
23. A method as claimed by any one of Claims 14 to 22, comprising
administering an effective amount of tirzepatide or a pharmaceutically acceptable salt
thereof, to the patient once weekly, wherein the method results in a reduction in the risk
30 of death from HFpEF.
24. The method as claimed by any one of claims 14 to 23 wherein the patient's
six minute walk test is improved by about 10%.
24
25. The method as claimed by any one of Claims 14 to 24, wherein the
patient's risk of the occurrence of a composite of the following outcomes is reduced:
cognitive decline, hospitalization for HFpEF, or death.
26. The method as claimed by any one of Claims 14 to 25 wherein the
5 therapeutically effective amount oftirzepatide is selected from the group consisting of
about 5.0 mg, about 10.0 mg and about 15.0 mg.
27. The method of claim 26 wherein the therapeutically effective amount of
tirzepatide is about 15.0 mg.
28. The method as claimed by any one of Claims 14 to 27 wherein once
10 weekly administration oftirzepatide is continued for at least 2 years.
29. The method as claimed by any one of Claims 14 to 28 wherein the patient
has either: multiple cardiovascular risk factors without established cardiovascular disease;
or established cardiovascular disease.