U.S. patent application number 17/736116 was filed with the patent office on 2022-09-08 for glp-1 receptor agonists in dementia.
The applicant listed for this patent is Novo Nordisk A/S. Invention is credited to Sarah Friedrich, Charlotte Christine Thim Hansen, Lotte Bjerre Knudsen, Anna Secher.
Application Number | 20220280612 17/736116 |
Document ID | / |
Family ID | 1000006408702 |
Filed Date | 2022-09-08 |
United States Patent
Application |
20220280612 |
Kind Code |
A1 |
Friedrich; Sarah ; et
al. |
September 8, 2022 |
GLP-1 RECEPTOR AGONISTS IN DEMENTIA
Abstract
The present invention relates to improved medical therapies for
all forms and stages of dementia involving administration of (i)
GLP-1 receptor agonists to subjects with metabolic syndrome or (ii)
semaglutide.
Inventors: |
Friedrich; Sarah;
(Goettingen, DE) ; Hansen; Charlotte Christine Thim;
(Soeborg, DK) ; Knudsen; Lotte Bjerre; (Jerslev,
DK) ; Secher; Anna; (Koebenhavn NV, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novo Nordisk A/S |
Bagsvaerd |
|
DK |
|
|
Family ID: |
1000006408702 |
Appl. No.: |
17/736116 |
Filed: |
May 4, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/EP2020/081087 |
Nov 5, 2020 |
|
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17736116 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61P 25/28 20180101; A61K 38/26 20130101 |
International
Class: |
A61K 38/26 20060101
A61K038/26; A61K 9/20 20060101 A61K009/20; A61P 25/28 20060101
A61P025/28 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 6, 2019 |
EP |
19207501.8 |
Jul 20, 2020 |
EP |
20186623.3 |
Claims
1. A method for treating Alzheimer's disease, comprising
administering semaglutide to a subject in need thereof.
2. The method according to claim 1, wherein the subject has mild
cognitive impairment or mild dementia.
3. The method according to claim 1, wherein the semaglutide is the
sole pharmaceutically active ingredient administered to the
subject.
4. The method according to claim 1, wherein the semaglutide is
administered subcutaneously.
5. The method according to claim 1, wherein the semaglutide is
administered orally.
6. The method according to claim 1, wherein the semaglutide is
administered in a tablet comprising a salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
7. The method according to claim 1, further comprising
administering the semaglutide for at least 12 months.
8. The method according to claim 6, wherein the salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodium
N-(8-(2-hydroxybenzoyl)amino)caprylate.
9. The method according to claim 2, wherein the subject has mild
cognitive impairment.
10. The method according to claim 9, wherein the semaglutide is
administered subcutaneously.
11. The method according to claim 9, wherein the semaglutide is
administered orally.
12. The method according to claim 9, wherein the semaglutide is
administered in a tablet comprising a salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
13. The method according to claim 12, wherein the salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodium
N-(8-(2-hydroxybenzoyl)amino)caprylate.
14. The method according to claim 2, wherein the subject has mild
dementia.
15. The method according to claim 14, wherein the semaglutide is
administered subcutaneously.
16. The method according to claim 14, wherein the semaglutide is
administered orally.
17. The method according to claim 14, wherein the semaglutide is
administered in a tablet comprising a salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
18. The method according to claim 17, wherein the salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodium
N-(8-(2-hydroxybenzoyl)amino)caprylate.
19. The method according to claim 3, wherein the semaglutide is
administered subcutaneously.
20. The method according to claim 3, wherein the semaglutide is
administered orally.
21. The method according to claim 3, wherein the semaglutide is
administered in a tablet comprising a salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
22. The method according to claim 21, wherein the salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodium
N-(8-(2-hydroxybenzoyl)amino)caprylate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of International
Application PCT/EP2020/081087 (WO 2021/089678), filed Nov. 5, 2020,
which claims priority to European Patent Application 19207501.8,
filed Nov. 6, 2019 and European Patent Application 20186623.3 filed
Jul. 20, 2020; the contents of which are incorporated herein by
reference.
INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING
[0002] The instant application contains a sequence listing which
has been submitted in ascii format via efs-web and is hereby
incorporated by reference in its entirety. Said ascii copy, created
on May 3, 2022, is named "190095US01_sequence_listing_st25", and is
1 kilobytes in size
BACKGROUND
[0003] No treatment options are currently available to actively
prevent or slow progression to dementia and no new pharmacological
therapies have been approved for the treatment of dementia within
the last 20 years. According to WHO, approximately 50 million
people worldwide have dementia, this number is projected to triple
by 2050, and Alzheimer's disease is the most common form of
dementia and may contribute to 60-70% of cases. Intensive efforts
have so far failed to identify any medical treatments that prevent,
delay, or modify the disease course of dementia, including recent
unsuccessful trials focusing on reducing production or enhancing
clearance of amyloid-.beta.. Thus, improved pharmacological
therapies for patients with dementia are desired. It is an
important unanswered question to determine whether GLP-1 receptor
agonists have an effect on dementia in humans.
SUMMARY
[0004] The present invention relates to improved medical therapies
for dementia involving administration of GLP-1 receptor
agonists.
[0005] In some embodiments the invention relates to methods for the
treatment of dementia, wherein said method comprises administering
a GLP-1 receptor agonist to a subject in need thereof, said subject
has metabolic syndrome, and said GLP-1 receptor agonist comprises
GLP-1 (7-37) (SEQ ID No: 1) optionally comprising one or more
substitutions, deletions, additions and/or modifications.
[0006] In some embodiments the invention relates to methods for the
treatment of dementia, wherein said method comprises administering
semaglutide to a subject in need thereof.
BRIEF DESCRIPTION OF DRAWINGS
[0007] FIG. 1 shows time to dementia with GLP-1 receptor agonists
versus placebo in pooled RCTs; in the pooled RCTs, 15 patients
randomized to a GLP-1 receptor agonist (0.66 per 1000
patient-years) and 32 patients randomized to placebo (1.41 per 1000
patient-years) developed dementia. GLP-1 RA=GLP-1 receptor
agonists.
[0008] FIG. 2 shows hazard ratios for dementia with each 1 year
increase in exposure duration to GLP-1 receptor agonists and other
second-line diabetes treatments in the nationwide cohort. Cox
proportional hazards regression models conducted for exposure to
each treatment. Estimates denote the hazard ratio for a 1 year
increase in duration of exposure. The models were adjusted for
history of stroke, myocardial infarction, hypertension, educational
attainment, and diabetes duration. Sex, age, and calendar date were
included via matching.
[0009] FIG. 3 shows hazard ratios for dementia with each 1 year
increase in exposure duration to GLP-1 receptor agonists according
to subgroup in the nationwide cohort. Cox proportional hazards
regression models conducted for exposure to GLP-1 in various
subgroups. Estimates denote the hazard ratio for a 1 year increase
in duration of exposure. The models were adjusted for history of
stroke, myocardial infarction, hypertension, educational
attainment, and diabetes duration. Sex, age, and calendar date were
included via matching.
[0010] FIG. 4 shows study design used in the nationwide cohort.
*First ever second-line diabetes treatment=first treatment with
diabetes treatment not including metformin, eligible=eligible for
cohort of diabetes patients, case date=date of dementia diagnosis
with matching of each case to ten controls without dementia,
exposure window 5-year window prior to case date, where duration of
cumulative diabetes treatment is assessed.
[0011] FIG. 5A shows hazard ratios for dementia with each 1 year
increase in exposure duration to GLP-1 receptor agonists and other
second-line diabetes. Treatments in the Nationwide Cohort Excluding
the Last 2 Years Prior to Case Date. Cox proportional hazards
regression models conducted for exposure to each treatment.
Estimates denote the hazard ratio for a 1 year increase in duration
of exposure. The models were adjusted for history of stroke,
myocardial infarction, hypertension, educational attainment, and
diabetes duration. Sex, age, and calendar date were included via
matching.
[0012] FIG. 5B shows hazard ratios for dementia with each 1 year
increase in exposure duration to GLP-1 receptor agonists and other
second-line diabetes Treatments in the Nationwide Cohort, where
Diabetes Duration was Defined as "Time Since First Treatment with
Metformin or Second-line Diabetes Treatment". Cox proportional
hazards regression models conducted for exposure to each treatment.
Estimates denote the hazard ratio for a 1 year increase in duration
of exposure. The models were adjusted for history of stroke,
myocardial infarction, hypertension, educational attainment, and
diabetes duration. Sex, age, and calendar date were included via
matching.
[0013] FIG. 6A shows hazard ratios for dementia with each 1 year
increase in exposure duration to GLP-1 receptor agonists assessed
3, 5, and 10 years before diagnosis of dementia in the nationwide
cohort. *Primary analysis. Cox proportional hazards regression
models conducted for GLP-1 receptor agonist exposure and assessed
during a 3, 5, and 10-year exposure window prior to dementia.
Estimates denote the hazard ratio for a 1 year increase in duration
of exposure. The models were adjusted for history of stroke,
myocardial infarction, hypertension, educational attainment, and
diabetes duration. Sex, age, and calendar date were included via
matching.
[0014] FIG. 6B shows hazard ratio for dementia with each 1 year
increase in exposure duration to GLP-1 receptor agonist exposure in
the nationwide cohort adjusted for age, sex, and calendar date via
matching. Cox proportional hazards regression model conducted for
exposure to GLP-1 receptor agonists. The estimate denotes the
hazard ratio for a 1 year increase in duration of exposure. The
model was adjusted sex, age, and calendar date via matching.
[0015] FIG. 6C shows hazard ratio for competing risk of death with
each 1 year increase in exposure duration to GLP-1 receptor agonist
in the nationwide cohort. Cox proportional hazards regression model
conducted for exposure to GLP-1 receptor agonists. The estimate
denotes the hazard ratio for a 1 year increase in duration of
exposure. The model was adjusted for history of stroke, myocardial
infarction, hypertension, educational attainment, and diabetes
duration. Sex, age, and calendar date were included via
matching.
[0016] FIG. 7 shows effect on Y-maze alternation behaviour in SAMP8
mice administration of semaglutide compared to vehicle.
[0017] FIGS. 8 and 9 show improvement of long-term memory in SAMP8
mice as measured in the step-through passive avoidance test
following administration of semaglutide compared to vehicle and
presenting step-through latency (FIG. 8) and escape latency (FIG.
9).
[0018] FIG. 10 shows effect of semaglutide in a lipopolysaccharide
(LPS)-induced neuroinflammation, a non-genetic model of Alzheimer's
disease in rodents, on the microglial inflammatory marker Iba1 in
the hippocampus.
DESCRIPTION
[0019] The present inventors surprisingly found that administration
of glucagon-like peptide 1 (GLP-1) receptor agonists reduced the
risk of dementia in subjects with metabolic syndrome. Furthermore,
the inventors surprisingly found that semaglutide improved dementia
in animal models.
[0020] In some embodiments the invention relates to a method for
the treatment of dementia, wherein said method comprises
administering a GLP-1 receptor agonist to a subject in need thereof
and said subject has metabolic syndrome. In some embodiments the
invention relates to a method for the treatment of dementia,
wherein said method comprises administering a GLP-1 receptor
agonist to a human subject in need thereof and said subject has one
or more indications selected from the group consisting of
pre-diabetes, diabetes, cardiovascular disease, obesity, and
hypertension. In some embodiments the invention relates to a method
for the treatment of dementia, wherein said method comprises
administering semaglutide to a subject in need thereof.
[0021] In some embodiments the invention relates to a method for
reducing the risk of developing dementia, wherein said method
comprises administering a GLP-1 receptor agonist to a subject in
need thereof and said subject has metabolic syndrome. In some
embodiments the invention relates to a method for reducing the risk
of developing dementia, wherein said method comprises administering
a GLP-1 receptor agonist to a subject in need thereof and said
subject has one or more indications selected from the group
consisting of pre-diabetes, diabetes, cardiovascular disease,
obesity, and hypertension. In some embodiments the invention
relates to a method for reducing the risk of developing dementia,
wherein said method comprises administering semaglutide to a
subject in need thereof.
[0022] Dementia exists in different degrees of severity. In some
embodiments, the term "dementia" as used herein refers to all forms
of and stages of the dementia disease continuum. In some
embodiments dementia is selected from the group of indications
defined in ICD-11: Dementia due to Alzheimer disease; Dementia due
to Alzheimer disease with early onset; Autosomal dominant Alzheimer
disease dementia, mutation of presenilin 1; Autosomal dominant
Alzheimer disease dementia, mutation of presenilin 2; Autosomal
dominant Alzheimer disease dementia, mutation of amyloid precursor
protein; Dementia due to Alzheimer disease with late onset;
Alzheimer disease dementia, mixed type, with cerebrovascular
disease; Alzheimer disease dementia, mixed type, with other
nonvascular aetiologies; Non-amnestic Alzheimer disease dementia
subtypes; Non-amnestic Alzheimer disease dementia, logopenic
variant; Non-amnestic Alzheimer's disease, logopenic variant with
primary progressive aphasia; Non-amnestic Alzheimer disease
dementia, visuospatial variant; Non-amnestic Alzheimer's disease,
visuospatial variant with posterior cortical atrophy; Non-amnestic
Alzheimer disease dementia, frontal variant; Alzheimer disease
dementia with psychosis; Alzheimer disease dementia with
depression; Dementia due to cerebrovascular disease; Vascular
dementia haemorrhagic subtype; Vascular dementia ischaemic subtype;
Multi-infarct dementia; Single strategic infarct dementia; Dementia
due to subcortical vascular encephalopathy; Dementia due to hypoxic
encephalopathy; Dementia due to genetic causes; Dementia due to
central nervous system vasculitides; Dementia due to hypertensive
encephalopathy; Dementia due to intracerebral hypertensive
haemorrhage; Dementia due to cerebral amyloid angiopathy; Dementia
due to Lewy body disease; Frontotemporal dementia; Frontotemporal
dementia, behavioural variant; Frontotemporal dementia, language
variant; Frontotemporal dementia, non-fluent or agrammatic variant;
Frontotemporal dementia, semantic variant; Frontotemporal dementia,
logopenic variant; Frontotemporal dementia with motor neuron
disease; Frontotemporal dementia with familial inclusion body
myopathy with Paget's disease of bone; Frontotemporal dementia due
to genetic mutation; Frontotemporal dementia due to C9orf72
mutation; Frontotemporal dementia due to MAPT mutation;
Frontotemporal dementia due to VCP mutation; Frontotemporal
dementia due to GRN mutation; Frontotemporal dementia due to CHMP2B
mutation; Frontotemporal dementia due to FUS mutation;
Frontotemporal dementia due to TARDBP mutation; Frontotemporal
dementia due to other or new mutations; Dementia due to
psychoactive substances including medications; Dementia due to use
of alcohol; Dementia due to use of sedatives, hypnotics or
anxiolytics; Posthallucinogen perception disorder; Dementia due to
use of volatile inhalants; Post radiation dementia; Dementia due to
carbon monoxide poisoning; Dementia due to drug intoxication;
Dementia or parkinsonism due to manganese toxicity; Dementia due to
diseases classified elsewhere; Dementia due to certain specified
central nervous system degenerative diseases; Dementia due to
Parkinson disease; Dementia due to Huntington disease; Dementia due
to corticobasal degeneration; Dementia due to progressive
supranuclear palsy; Dementia due to neurofilament inclusion body
disease; Dementia due to progressive subcortical gliosis; Dementia
due to multiple system atrophy; Dementia due to spinocerebellar
ataxia; Dementia due to neurodegeneration with brain iron
accumulation; Dementia due to leukodystrophy; Dementia due to
Parkinsonism-dementia complex of Guam; Dementia due to certain
specified infectious diseases; Dementia due to human
immunodeficiency virus; Dementia due to neurosyphilis; Dementia due
to herpes encephalitis; Dementia due to trypanosomiasis; Dementia
due to neurocysticercosis; Dementia due to Lyme disease; Dementia
due to Whipple disease; Dementia due to progressive multifocal
leukoencephalopathy; Certain specified primary degenerative
dementias; Neurofibrillary tangle dementia; Familial multiple
system tauopathy; Argyrophilic grain disease; Dementia due to
certain specified disorders of the central nervous system; Dementia
due to multiple sclerosis; Dementia due to prion disease; Dementia
due to sporadic Creutzfeldt-Jakob disease; Dementia due to variant
Creutzfeldt-Jakob disease; Dementia due to familial
Creutzfeldt-Jakob disease; Dementia due to iatrogenic
Creutzfeldt-Jakob disease; Dementia due to sporadic fatal insomnia;
Dementia due to fatal familial insomnia; Dementia due to
Gerstmann-Staussler-Sheinker syndrome; Dementia due to Kuru;
Dementia due to acute demyelinating encephalomyelitis; Dementia due
to subacute sclerosing panencephalitis; Dementia due to Hashimoto's
encephalopathy; Dementia due to paraneoplastic encephalitis;
Dementia due to autoimmune encephalitis; Dementia due to primary
central nervous system neoplasm; Dementia due to metastatic brain
tumour; Dementia due to epilepsy; Dementia due to normal pressure
hydrocephalus; Dementia due to metabolic disorders involving the
brain; Dementia due to injury to the head; Dementia due to chronic
subdural haematoma; Dementia due to obstructive hydrocephalus;
Dementia due to exposure to heavy metals and other toxins; Dementia
due to nutritional deficiency; Dementia due to thiamine deficiency;
Dementia due to vitamin B12 deficiency; Dementia due to folate
deficiency; Dementia due to vitamin E deficiency; Dementia due to
iron deficiency; Dementia due to other nutritional deficiency;
Dementia due to pellagra; Dementia due to metabolic abnormalities;
Dementia due to hypercalcaemia; Dementia due to acquired
hypothyroidism; Dementia due to Wilson disease; Dementia due to
dialysis; Dementia due to hepatic failure; Dementia due to renal
failure; Dementia due to chromosomal anomalies; Dementia due to
Down syndrome; Dementia due to Fragile X Syndrome; Dementia due to
rheumatological diseases; Dementia due to polyarteritis nodosa;
Dementia due to systemic lupus erythematosus; Dementia due to
Behcet disease; Dementia due to certain specified cause;
Behavioural or psychological disturbances in dementia; Psychotic
symptoms in dementia; Mood symptoms in dementia; Anxiety symptoms
in dementia; Apathy in dementia; Agitation or aggression in
dementia; Disinhibition in dementia; Wandering in dementia; End
stage dementia; Degenerative dementia; Presenile psychotic mental
disorder; Paranoid dementia; Presenile dementia not otherwise
specified; Senile dementia; and Old age dementia. In some
embodiments dementia is selected from the group consisting of mild
cognitive impairment, Alzheimer's disease, mixed dementia, vascular
dementia, dementia with Lewy bodies, frontotemporal dementia,
pre-senile dementia, and senile dementia. In some embodiments
dementia is the Alzheimer's continuum with mild cognitive
impairment or mild dementia. In some embodiments dementia is mild
cognitive impairment, such as mild cognitive impairment of the
Alzheimer's type. In some embodiments dementia is Alzheimer's
disease, such as preclinical Alzheimer's disease, mild cognitive
impairment of the Alzheimer's type, early onset familial
Alzheimer's disease, or prodromal Alzheimer's disease. In some
embodiments dementia is mild cognitive impairment of the
Alzheimer's type. In some embodiments dementia is mixed dementia.
In some embodiments dementia is vascular dementia. In some
embodiments dementia is dementia with Lewy bodies. In some
embodiments dementia is frontotemporal dementia. In some
embodiments dementia is pre-senile dementia. In some embodiments
dementia is senile dementia.
[0023] In some embodiments, the term "treatment" as used herein
encompasses preventing, delaying, reducing the risk of developing,
ameliorating, or curatively treating the medical indication
referred to. Treatment may be symptomatic treatment or disease
modifying treatment. In some embodiments, the term treatment as
used herein refers to preventing the medical indication referred
to. In some embodiments, the term treatment as used herein refers
to delaying (e.g. delaying the onset of) the medical indication
referred to. In some embodiments, the term treatment as used herein
refers to reducing the risk of developing the medical indication
referred to. In some embodiments, the term treatment as used herein
refers to ameliorating the medical indication referred to. In some
embodiments, the term treatment as used herein refers to curatively
treating the medical indication referred to.
Subpopulation
[0024] The subject to be administered GLP-1 receptor agonists
according to the present invention may be human, such as an adult
human (also referred to as adults). In some embodiments the subject
has metabolic syndrome. As used herein, the term "metabolic
syndrome" refers to one or more indications selected from the group
consisting of pre-diabetes, diabetes, cardiovascular disease,
obesity, and hypertension. In some embodiments "metabolic syndrome"
refers to at least two indications selected from the group
consisting of pre-diabetes, diabetes, cardiovascular disease,
obesity, and hypertension. In some embodiments "metabolic syndrome"
refers to at least three indications selected from the group
consisting of pre-diabetes, diabetes, cardiovascular disease,
obesity, and hypertension. In some embodiments the subject has
pre-diabetes. In some embodiments the subject has diabetes. In some
embodiments diabetes is type 2 diabetes. In some embodiments the
subject has obesity. In some embodiments the subject has
cardiovascular disease. In some embodiments the subject has
obesity. In some embodiments obesity is a BMI of at least 25
kg/m.sup.2, such as at least 27 kg/m.sup.2 or at least 30
kg/m.sup.2. In some embodiments the subject has hypertension. In
some embodiments cardiovascular disease includes one or more of
coronary artery disease (such as angina and myocardial infarction),
stroke, heart failure, hypertensive heart disease, rheumatic heart
disease, cardiomyopathy, abnormal heart rhythms, congenital heart
disease, valvular heart disease, carditis, aortic aneurysms,
peripheral artery disease, thromboembolic disease, and venous
thrombosis. In some embodiments the subject has previously been
administered insulin.
GLP-1 Receptor Agonists
[0025] The term "GLP-1 receptor agonist" as used herein refers to a
compound, which fully or partially activates the human GLP-1
receptor. In some embodiments, the GLP-1 receptor agonist for use
in the present invention is an acylated GLP-1 receptor agonist. The
term "acylated" as used in relation to GLP-1 receptor agonists
refers to the GLP-1 receptor agonist having covalently attached at
least one substituent comprising a lipophilic moiety, such as a
fatty acid or a fatty diacid. In some embodiments the substituent
comprises a fatty acid or a fatty diacid. In some embodiments, the
term GLP-1 receptor agonist as well as the specific GLP-1 receptor
agonists described herein also encompass salt forms thereof.
[0026] It follows that the GLP-1 receptor agonist should display
"GLP-1 activity" which refers to the ability of the compound, i.e.
GLP-1 receptor agonist, to bind to the GLP-1 receptor and initiate
a signal transduction pathway resulting in insulinotropic action or
other physiological effects as is known in the art. In some
embodiments the "GLP-1 receptor agonist" binds to a GLP-1 receptor,
e.g., with an affinity constant (K.sub.D) or activate the receptor
with a potency (EC.sub.50) of below 1 .mu.M, e.g. below 100 nM as
measured by methods known in the art (see e.g. WO 98/08871) and
exhibits insulinotropic activity, where insulinotropic activity may
be measured in vivo or in vitro assays known to those of ordinary
skill in the art. For example, the GLP-1 receptor agonist may be
administered to an animal with increased blood glucose (e.g.
obtained using an Intravenous Glucose Tolerance Test (IVGTT). A
person skilled in the art will be able to determine a suitable
glucose dosage and a suitable blood sampling regime, e.g. depending
on the species of the animal, for the IVGTT) and measure the plasma
insulin concentration over time. Suitable assays have been
described in such as WO2015/155151.
[0027] The term half maximal effective concentration (EC.sub.50)
generally refers to the concentration which induces a response
halfway between the baseline and maximum, by reference to the dose
response curve. EC.sub.50 is used as a measure of the potency of a
compound and represents the concentration where 50% of its maximal
effect is observed. Due to the albumin binding effects of GLP-1
receptor agonists comprising a substituent as described herein, it
is important to pay attention to if the assay includes human serum
albumin or not.
[0028] The in vitro potency of the GLP-1 receptor agonist may be
determined as described in WO2015/155151, Example 29 without Human
Serum Albumin (HSA), and the EC.sub.50 determined. The lower the
EC.sub.50 value, the better the potency. In some embodiments the
potency (EC50) as determined (without HSA) is 5-1000 pM, such as
10-750 pM, 10-500 pM or 10-200 pM. In some embodiments the EC50
(without HSA) is at most 500 pM, such as at most 300 pM, such as at
most 200 pM. In some embodiments the EC50 (without HSA) is
comparable to human GLP-1(7-37). In some embodiments the EC50
(without HSA) is at most 50 pM. In a further such embodiment the
EC50 is at most 40 pM, such as at most 30 pM such as at most 20 pM,
such as at most 10 pM. In some embodiments the EC50 is about 10
pM.
[0029] Also, or alternatively, the binding of the GLP-1 receptor
agonist to albumin may be measured using the in vitro potency assay
of Example 29 in WO2015/155151 including HSA. An increase of the in
vitro potency, EC.sub.50 value, in the presence of serum albumin
reflects the affinity to serum albumin. In some embodiments the
potency (EC50) as determined (with 1% HSA) is 5-1000 pM, such as
100-750 pM, 200-500 pM or 100-400 pM. In some embodiments the EC50
(with 1% HSA) is at most 750 pM, such as at most 500 pM, such as at
most 400 pM, such as at most 300 or such as at most 250 pM.
[0030] If desired, the fold variation in relation to a known GLP-1
receptor agonist may be calculated as EC50(test
compound)/EC50(known compound), and if this ration is such as
0.5-1.5, or 0.8-1.2 the potencies are considered to be equivalent.
In some embodiments the potency, EC50 (without HSA), is equivalent
to the potency of liraglutide. In some embodiments the potency,
EC50 (without HSA), is equivalent to the potency of semaglutide. In
some embodiments the potency, EC50 (with 1% HSA), is equivalent to
the potency of liraglutide. In some embodiments the potency, EC50
(with 1% HSA), is equivalent to the potency of semaglutide.
[0031] In some embodiments the GLP-1 receptor agonist comprises one
or more substitutions, deletions, additions and/or modifications.
In some embodiments a modification is a covalently attached
substituent. In some embodiments the GLP-1 receptor agonist
comprises a peptide which is the human GLP-1 (GLP-1(7-37)) or a
variant thereof. Human GLP-1, also referred to herein as
"GLP-1(7-37)", has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG
(SEQ ID No: 1). In some embodiments the term "variant" refers to a
compound which comprises one or more amino acid substitutions,
deletions, additions and/or modifications. Such addition or
deletion of amino acid residues may take place at the N-terminal of
the peptide and/or at the C-terminal of the peptide. In some
embodiments a simple nomenclature is used to describe the GLP-1
receptor agonist, e.g., [Aib8] GLP-1(7-37) designates a GLP-1(7-37)
receptor agonist wherein the naturally occurring Ala in position 8
has been substituted with Aib. In some embodiments the GLP-1
receptor agonist comprises a maximum of 12 amino acids which have
been altered, e.g., by substitution, deletion, insertion and/or
modification, compared to GLP-1(7-37) (SEQ ID No: 1). In some
embodiments the GLP-1 receptor agonist comprises a maximum of 10
amino acids which have been altered, e.g., by substitution,
deletion, insertion and/or modification, compared to GLP-1(7-37)
(SEQ ID No: 1). In some embodiments the GLP-1 receptor agonist
comprises a maximum of 9 amino acids which have been altered, e.g.,
by substitution, deletion, insertion and/or modification, compared
to GLP-1(7-37) (SEQ ID No: 1). In some embodiments the GLP-1
receptor agonist comprises a maximum of 8 amino acids which have
been altered, e.g., by substitution, deletion, insertion and/or
modification, compared to GLP-1(7-37) (SEQ ID No: 1). In some
embodiments the GLP-1 receptor agonist comprises a maximum of 7
amino acids which have been altered, e.g., by substitution,
deletion, insertion and/or modification, compared to GLP-1(7-37)
(SEQ ID No: 1). In some embodiments the GLP-1 receptor agonist
comprises a maximum of 6 amino acids which have been altered, e.g.,
by substitution, deletion, insertion and/or modification, compared
to GLP-1(7-37) (SEQ ID No: 1). In some embodiments the GLP-1
receptor agonist comprises a maximum of 5 amino acids which have
been altered, e.g., by substitution, deletion, insertion and/or
modification, compared to GLP-1(7-37) (SEQ ID No: 1). In some
embodiments the GLP-1 receptor agonist comprises a maximum of 4
amino acids which have been altered, e.g., by substitution,
deletion, insertion and/or modification, compared to GLP-1(7-37)
(SEQ ID No: 1). In some embodiments the GLP-1 receptor agonist
comprises a maximum of 3 amino acids which have been altered, e.g.,
by substitution, deletion, insertion and/or modification, compared
to GLP-1(7-37) (SEQ ID No: 1). In some embodiments the GLP-1
receptor agonist comprises a maximum of 2 amino acids which have
been altered, e.g., by substitution, deletion, insertion and/or
modification, compared to GLP-1(7-37) (SEQ ID No: 1). Unless
otherwise stated the GLP-1 comprises only L-amino acids.
[0032] In some embodiments the GLP-1 receptor agonist exhibits at
least 60%, 65%, 70%, 80% or 90% sequence identity to GLP-1(7-37)
over the entire length of GLP-1(7-37). As an example of a method
for determination of sequence identity between two compounds, the
two peptides [Aib8]GLP-1(7-37) and GLP-1(7-37) are aligned. The
sequence identity of [Aib8]GLP-1(7-37) relative to GLP-1(7-37) is
given by the number of aligned identical residues minus the number
of different residues divided by the total number of residues in
GLP-1(7-37). Accordingly, in said example the sequence identity is
(31-1)/31.
[0033] In some embodiments the C-terminal of the GLP-1 receptor
agonist is an amide. In some embodiments the GLP-1 receptor agonist
is GLP-1(7-37) or GLP-1(7-36)amide.
[0034] In order to prolong the effect of the GLP-1 receptor agonist
it is preferred that the GLP-1 receptor agonist have an extended
half-life. The half-life can be determined by method known in the
art an in an appropriate model, such as in Male Sprague Dawley rats
or minipigs as described in WO2012/140117. Half-life in rats may be
determined as in Example 39 and the half-life in minipigs may be
determined as in Example 37 therein.
[0035] In some embodiments the GLP-1 receptor agonist according to
the invention has a half-life above 2 hours in rat. In some
embodiments the GLP-1 receptor agonist according to the invention
has a half-life above 4 hours, such as above 6 hours, such as above
8 hours, such as above 10 hours, such as above 12 hours or such as
above 15 hours in rat.
[0036] In some embodiments the GLP-1 receptor agonist according to
the invention has a half-life above 24 hours in minipig. In some
embodiments the GLP-1 receptor agonist according to the invention
has a half-life above 30 hours, such as above 36 hours, such as
above 42 hours, such as above 48 hours, such as above 54 hours or
such as above 60 hours in minipig.
[0037] In some embodiments the GLP-1 receptor agonist has a
molecular weight of at most 12 000, such as at most 7 500 Da, such
as at most 5 000 Da. In some embodiments the GLP-1 receptor agonist
has a molar mass of at most 10 000 g/mol, such as at most 8 000
g/mol, such as at most 6 000 g/mol.
[0038] In some embodiments the GLP-1 receptor agonist comprises one
or two substituents which are covalently attached to the peptide
and wherein said substituent comprises a lipophilic moiety. In some
embodiments the substituent comprises a fatty acid or a fatty
diacid. In some embodiments the substituent comprises a C16, C18 or
C20 fatty acid. In some embodiments the substituent comprises a
C16, C18 or C20 fatty diacid.
[0039] In some embodiments the substituent comprises formula
(X)
##STR00001##
wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or
19. In some embodiments the substituent comprises formula (X),
wherein n is in the range of 13 to 19, such as in the range of 13
to 17. In some embodiments the substituent comprises formula (X),
wherein n is 13, 15 or 17. In some embodiments the substituent
comprises formula (X), wherein n is 13. In some embodiments the
substituent comprises formula (X), wherein n is 15. In some
embodiments the substituent comprises formula (X), wherein n is 17.
In some embodiments the substituent comprises formula (XIa)
[0040] HOOC--(C.sub.6H.sub.4)--O--(CH.sub.2).sub.m--CO-* (XIa),
wherein m is an integer in the range of 6-14. In some embodiments
the substituent comprises formula (XIb)
##STR00002##
wherein the carboxy group is in position 2, 3 or 4 of the
(C.sub.6H.sub.4) group and wherein m is an integer in the range of
8-11. In some embodiments the substituent comprises formula (XIa)
or formula (XIb), wherein m is in the range of 6 to 14, such as in
the range of 8 to 11. In some embodiments the substituent comprises
formula (XIa) or formula (XIb), wherein m is 8, 10 or 12. In some
embodiments the substituent comprises formula (XIa) or formula
(XIb), wherein m is 9. In some embodiments the substituent
comprises formula (XIa) or formula (XIb), wherein m is 11.
[0041] In some embodiments the substituent comprises a linker (also
referred to as a spacer) located proximally in said substituent to
the point of attachment between said substituent and the peptide in
the GLP-1 receptor agonist. In some embodiments the substituent
comprises a linker located proximally in said substituent to the
point of attachment between said substituent and the peptide in
said GLP-1 receptor agonist. In some embodiments the substituent
comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as
two OEG. The one or more OEG may be a linker.
[0042] In some embodiments the substituent is
[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyryla-
mino]ethoxy}ethoxy)acetylamino]ethoxy} ethoxy)acetyl]. In some
embodiments the substituent is
[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)
butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]. In
some embodiments the substituent is
[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamin-
o)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]-
ethoxy}ethoxy)acetyl]. In some embodiments the substituent is
{2-[2-(2-{2-[2-(2-{(S)-4-Carboxy-4-[10-(4-carboxyphenoxy)
decanoylamino]butyrylamino}-ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acety-
l}. In some embodiments the substituent is
{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)
decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acety-
l}. In some embodiments the substituent is
[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)
decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ac-
etyl].
[0043] In some embodiments the substituent comprises serum albumin,
such as human serum albumin. In some embodiments the substituent
comprises an immunoglobulin domain or fragment, such as a Fc domain
or a modified IgG4 Fc domain.
[0044] In some embodiments the GLP-1 receptor agonist is selected
from the group consisting of liraglutide, semaglutide, Compound A,
and Compound B. In some embodiments the GLP-1 receptor agonist is
liraglutide. Liraglutide is the GLP-1 receptor agonist
Arg34,Lys26-(N-epsilon-(gamma-L-glutamyl(N-alfa-hexadecanoyl)))-GLP-1(7-3-
7). Liraglutide may be prepared as described in Example 37 of
WO98/08871. In some embodiments the GLP-1 receptor agonist is
semaglutide. Semaglutide is the GLP-1 receptor agonist
N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylam-
ino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}
ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37). Semaglutide may be prepared
as described in Example 4 of WO2006/097537. In some embodiments the
GLP-1 receptor agonist is Compound A, which is diacylated
[Aib8,Arg34,Lys37]GLP-1(7-37) as shown in Example 2 of
WO2011/080103 and named
N.sup..epsilon.26-{2-[2-(2-{2[2-(2-{(S)-4-Carboxy-4-[10-(4-carboxyp-
henoxy)decanoylamino]butyrylamino}-ethoxy)ethoxy]acetylamino}ethoxy)
ethoxy]acetyl},
N.sup..epsilon.37-{2-[2-(2-{2[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy-
)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acety-
l}-[Aib.sup.8,Arg.sup.34,Lys.sup.37]GLP-1(7-37)-peptide. In some
embodiments the GLP-1 receptor agonist is Compound B which is
Diacylated
[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly
as shown in Example 31 of WO2012/140117 and named
N.sup..epsilon.27-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphe-
noxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy-
]-acetyl],
N.sup..epsilon.36-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4--
carboxyphenoxy)
decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]ac-
etyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-
-Gly. In some embodiments the GLP-1 receptor agonist is dulaglutide
or albiglutide.
[0045] In some embodiments, the GLP-1 receptor agonist is in the
form of a pharmaceutically acceptable salt, amide, or ester
thereof. In some embodiments the GLP-1 receptor agonist comprises
one or more pharmaceutically acceptable counter ions.
Pharmaceutical Composition
[0046] The GLP-1 receptor agonist may be administered in the form
of a pharmaceutical composition. The pharmaceutical composition may
be in a liquid or solid form.
Parenteral Administration
[0047] The pharmaceutical composition may comprise the GLP-1
receptor agonist in a concentration from 0.1 mg/ml to 100 mg/ml. In
some embodiments the pharmaceutical composition comprises 0.01-50
mg/ml, or 0.01-20 mg/ml, or 0.01-10 mg/ml GLP-1 receptor agonist.
In some embodiments the pharmaceutical composition comprises 0.1-20
mg/ml GLP-1 receptor agonist.
[0048] The pharmaceutical compositions described herein may further
comprise one or more pharmaceutically acceptable excipients, for
example selected from the group consisting of buffer system,
preservative, tonicity agent, chelating agent, stabilizer and
surfactant. In some embodiments the pharmaceutical composition
comprises one or more pharmaceutically acceptable excipients, such
as one or more selected from the group consisting of a buffer, an
isotonic agent, and a preservative. The formulation of
pharmaceutically active ingredients with various excipients is
known in the art, see e.g. Remington: The Science and Practice of
Pharmacy (e.g. 19th edition (1995), and any later editions). The
term "excipient" broadly refers to any component other than the
active therapeutic ingredient(s), e.g. the GLP-1 receptor agonist.
The excipient may be an inert substance, an inactive substance,
and/or a not medicinally active substance.
[0049] In some embodiments the pharmaceutical composition has a pH
in the range of 7.0-10.0, such as 7.0 to 9.5 or 7.2 to 9.5. In some
embodiments the pharmaceutical composition has a pH in the range of
7.0-8.5, such as 7.0 to 7.8 or 7.8 to 8.2. In some embodiments the
pharmaceutical composition has a pH of 7.4. In some embodiments the
pharmaceutical composition has a pH of 8.15. In some embodiments
the pharmaceutical composition comprises a phosphate buffer, such
as a sodium phosphate buffer, e.g. disodium phosphate. In some
embodiments the pharmaceutical composition comprises an isotonic
agent, such as propylene glycol. In some embodiments the
pharmaceutical composition comprises a preservative, such as
phenol.
[0050] The pharmaceutical composition may be in the form of a
solution or a suspension. In some embodiments the pharmaceutical
composition is aqueous composition, such as an aqueous solution or
an aqueous suspension. The term "aqueous composition" is defined as
a composition comprising at least 50% w/w water. Likewise, the term
"aqueous solution" is defined as a solution comprising at least 50%
w/w water, and the term "aqueous suspension" is defined as a
suspension comprising at least 50% w/w water. An aqueous
composition may comprise at least 50% w/w water, or at least 60%,
70%, 80%, or even at least 90% w/w of water.
[0051] In some embodiments the GLP-1 receptor agonist is
administered in the form of a pharmaceutical composition comprising
about 0.1-20 mg/ml GLP-1 receptor agonist, about 2-15 mM phosphate
buffer, about 2-25 mg/ml propylene glycol, and has a pH in the
range of 7.0-9.0. In some embodiments the GLP-1 receptor agonist is
administered in the form of a pharmaceutical composition comprising
about 0.1-20 mg/ml GLP-1 receptor agonist, about 2-15 mM phosphate
buffer, about 2-25 mg/ml propylene glycol, about 1-18 mg/ml phenol,
and has a pH in the range of 7.0-9.0. In some embodiments the GLP-1
receptor agonist (e.g. semaglutide) is administered in the form of
a pharmaceutical composition comprising about 1.34 mg/ml GLP-1
receptor agonist (e.g. semaglutide), about 1.42 mg/ml disodium
phosphate dihydrate, about 14.0 mg/ml propylene glycol, about 5.5
mg/ml phenol, and has pH of about 7.4. In some embodiments the
GLP-1 receptor agonist (e.g. semaglutide) is administered in the
form of a pharmaceutical composition comprising 1.34 mg/ml GLP-1
receptor agonist, 1.42 mg/ml disodium phosphate dihydrate, 14.0
mg/ml propylene glycol, 5.5 mg/ml phenol, and has pH of 7.4. In
some embodiments the GLP-1 receptor agonist (e.g. liraglutide) is
administered in the form of a pharmaceutical composition comprising
GLP-1 receptor agonist (e.g. 3-8 mg/ml), disodium phosphate
dihydrate, propylene glycol, phenol, and has pH of about 8.0-8.3.
In some embodiments the GLP-1 receptor agonist (e.g. liraglutide)
is administered in the form of a pharmaceutical composition
comprising GLP-1 receptor agonist (e.g. about 6.0 mg/ml), disodium
phosphate dihydrate, propylene glycol, phenol, and has pH of about
8.15.
Oral Administration
[0052] The solid composition may be a solid composition suited for
administration by the oral route as described further herein. In
some embodiments the solid composition comprises at least one
pharmaceutically acceptable excipient. The term "excipient" as used
herein broadly refers to any component other than the active
therapeutic ingredient(s) or active pharmaceutical ingredient(s)
(API(s)). The excipient may be a pharmaceutically inert substance,
an inactive substance, and/or a therapeutically or medicinally none
active substance. The excipient may serve various purposes, e.g. as
a carrier, vehicle, filler, binder, lubricant, glidant,
disintegrant, flow control agent, crystallization inhibitors
solubilizer, stabilizer, colouring agent, flavouring agent,
surfactant, emulsifier or combinations of thereof and/or to improve
administration, and/or absorption of the therapeutically active
substance(s) or active pharmaceutical ingredient(s). The amount of
each excipient used may vary within ranges conventional in the art.
Techniques and excipients which may be used to formulate oral
dosage forms are described in Handbook of Pharmaceutical
Excipients, 8th edition, Sheskey et al., Eds., American
Pharmaceuticals Association and the Pharmaceutical Press,
publications department of the Royal Pharmaceutical Society of
Great Britain (2017); and Remington: the Science and Practice of
Pharmacy, 22nd edition, Remington and Allen, Eds., Pharmaceutical
Press (2013). In some embodiments the excipients may be selected
from binders, such as polyvinyl pyrrolidone (povidone), etc.;
fillers such as cellulose powder, microcrystalline cellulose,
cellulose derivatives like hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose and
hydroxy-propylmethylcellulose, dibasic calcium phosphate, corn
starch, pregelatinized starch, etc.; lubricants and/or glidants
such as stearic acid, magnesium stearate, sodium stearylfumarate,
glycerol tribehenate, etc.; flow control agents such as colloidal
silica, talc, etc.; crystallization inhibitors such as Povidone,
etc.; solubilizers such as Pluronic, Povidone, etc.; colouring
agents, including dyes and pigments such as iron oxide red or
yellow, titanium dioxide, talc, etc.; pH control agents such as
citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic
calcium phosphate, dibasic sodium phosphate, etc.; surfactants and
emulsifiers such as Pluronic, polyethylene glycols, sodium
carboxymethyl cellulose, polyethoxylated and hydrogenated castor
oil, etc.; and mixtures of two or more of these excipients and/or
adjuvants.
[0053] The solid composition may comprise a binder, such as
povidone; starches; celluloses and derivatives thereof, such as
microcrystalline cellulose, e.g., Avicel PH from FMC (Philadelphia,
Pa.), hydroxypropyl cellulose hydroxylethyl cellulose and
hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp.
(Midland, Mich.); sucrose; dextrose; corn syrup; polysaccharides;
and gelatin. The binder may be selected from the group consisting
of dry binders and/or wet granulation binders. Suitable dry binders
are, e.g., cellulose powder and microcrystalline cellulose, such as
Avicel PH 102 and Avicel PH 200. In some embodiments the solid
composition comprises Avicel, such as Aavicel PH 102. Suitable
binders for wet granulation or dry granulation are corn starch,
polyvinyl pyrrolidone (povidon), vinylpyrrolidone-vinylacetate
copolymer (copovidone) and cellulose derivatives like
hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and hydroxyl-propylmethylcellulose. In some
embodiments the solid composition comprises povidone.
[0054] In some embodiments the solid composition comprises a filler
which may be selected from lactose, mannitol, erythritol, sucrose,
sorbitol, calcium phosphate, such as calciumhydrogen phosphate,
microcrystalline cellulose, powdered cellulose, confectioner's
sugar, compressible sugar, dextrates, dextrin and dextrose. In some
embodiments the solid composition comprises microcrystalline
cellulose, such as Avicel PH 102 or Avicel PH 200.
[0055] In some embodiments the solid composition comprises a
lubricant and/or a glidant. In some embodiments the composition
comprises a lubricant and/or a glidant, such as talc, magnesium
stearate, calcium stearate, zinc stearate, glyceryl behenate,
glyceryl debehenate, behenoyl polyoxyl-8 glycerides, polyethylene
oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate,
sodium oleate, sodium stearyl fumarate, stearic acid, hydrogenated
vegetable oils, silicon dioxide and/or polyethylene glycol etc. In
some embodiments the solid composition comprises magnesium stearate
or glyceryl debehenate (such as the product Compritol.RTM. 888
ATO).
[0056] In some embodiments the solid composition comprises a
disintegrant, such as sodium starch glycolate, polacrilin
potassium, sodium starch glycolate, crospovidon, croscarmellose,
sodium carboxymethylcellulose or dried corn starch. The solid
composition may comprise one or more surfactants, for example a
surfactant, at least one surfactant, or two different surfactants.
The term "surfactant" refers to any molecules or ions that are
comprised of a water-soluble (hydrophilic) part, and a fat-soluble
(lipophilic) part. The surfactant may e.g. be selected from the
group consisting of anionic surfactants, cationic surfactants,
nonionic surfactants, and/or zwitterionic surfactants.
[0057] The solid composition may further comprise a delivery agent
or absorption enhancer is for the present invention an excipient
capable of increasing the oral exposure of the GLP-1 receptor
agonist. The delivery agent may be a salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid (also referred to herein
as a salt of NAC), which contains the anion
N-(8-(2-hydroxybenzoyl)amino)caprylate. The structural formula of
N-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (I).
##STR00003##
[0058] In some embodiments the salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises one monovalent
cation, two monovalent cations or one divalent cation. In some
embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
is selected from the group consisting of the sodium salt, potassium
salt and/or calcium salt of of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments the
salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from
the group consisting of the sodium salt, potassium salt and/or the
ammonium salt. In some embodiments the salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid is the sodium salt or
the potassium salt. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate
may be prepared using the method described in e.g. WO96/030036,
WO00/046182, WO01/092206 or WO2008/028859. The salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline
and/or amorphous. In some embodiments the delivery agent comprises
the anhydrate, monohydrate, dihydrate, trihydrate, a solvate or one
third of a hydrate of the salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid as well as combinations
thereof. In some embodiments the delivery agent is a salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid as described in
WO2007/121318. In some embodiments the delivery agent is sodium
N-(8-(2-hydroxybenzoyl)amino)caprylate (referred to as "SNAC"
herein), also known as sodium 8-(salicyloylamino)octanoate.
[0059] In some embodiments the composition for use in the invention
is in the form of a solid composition, such as a tablet, for oral
administration.
[0060] In some embodiments the solid composition comprises the
GLP-1 receptor agonist in an amount in the range of 0.1-50 mg, such
as 0.5 to 40 mg or 1-30 mg. In some embodiments the solid
composition comprises the GLP-1 receptor agonist in an amount in
the range of 2-20 mg, such as 3-18 mg or 5-15 mg. In some
embodiments the solid composition comprises the GLP-1 receptor
agonist in an amount of about 3 mg, such as about 7 mg or about 14
mg.
[0061] In some embodiments least 30% (w/w) of the solid composition
(e.g. tablet) is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic
acid. In some embodiments least 50% (w/w) of the solid composition
(e.g. tablet) is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic
acid. In some embodiments the amount of the salt of
N-(8-(2-hydroxybenzoyl) amino)caprylic acid per dose unit of the
composition is in the range of 0.20-0.5 mmol, 0.25-1.0 mmol,
0.30-0.75 mmol, or such as 0.45-0.65 mmol. In some embodiments the
amount of SNAC in the composition is in the range of 75-600 mg. In
some embodiments the amount of SNAC in the composition is in the
range of 75-400 mg, such as from 80-350 mg, such as from about 100
to about 300 mg per dose unit.
[0062] In some embodiments the solid composition comprises a
lubricant, such as magnesium stearate. In some embodiments a unit
dose of the solid composition comprises: 0.1-50 mg GLP-1 receptor
agonist, 25-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic
acid (NAC) (such as the sodium salt of NAC (SNAC)), and 0-25 mg
lubricant.
Administration Regimen
[0063] GLP-1 receptor agonist may be administered in a
therapeutically effective amount, such as an amount therapeutically
effective to treat type 2 diabetes. The therapeutically effective
amount of GLP-1 receptor agonist can be assessed by a medical
doctor. The dosage of GLP-1 receptor agonist may be in the range
from 0.01 to 50 mg, such as 1-30 mg or 3-20 mg. In some embodiments
the GLP-1 receptor agonist is administered at any time in the
day.
[0064] The GLP-1 receptor agonist, such as semaglutide, may be
administered once weekly or more frequent, such as once daily.
[0065] In some embodiments the GLP-1 receptor agonist is
administered in an amount in the range of 0.05-30 mg per week, such
as 0.5 or 1.0 mg per week, optionally by once weekly
administration. In some embodiments the GLP-1 receptor agonist is
administered in an amount of at least 0.1 mg per week, such as at
least 0.5 mg per week or at least 1 mg per week, optionally by once
weekly administration. In some embodiments the GLP-1 receptor
agonist is administered in an amount of no more than 25 mg per
week, such as no more than 20 mg per week or no more than 15 mg per
week, optionally by once weekly administration. In some embodiments
the GLP-1 receptor agonist is administered in an amount of no more
than 10 mg per week, such as no more than 6 mg per week or no more
than 3 mg per week, optionally by once weekly administration. In
some embodiments the GLP-1 receptor agonist is administered once
weekly in an amount of 0.5 or 1.0 mg.
[0066] In some embodiments the method of the invention reduces the
risk of mortality.
[0067] In some embodiments the administration of a GLP-1 receptor
agonist is a chronic treatment in which semaglutide is administered
for at least 12 months, such as for at least 16 months or at least
18 months.
Parenteral Administration
[0068] The GLP-1 receptor agonist may be administered via
parenteral administration, for example subcutaneous injection.
GLP-1 receptor agonist may be administered using a pen-injector,
such as a 3 ml disposable pen-injector.
[0069] In some embodiments the dosage of GLP-1 receptor agonist is
in the range from 0.1 to 5.0 mg, such as in the range from 0.1 to
3.0 mg. In some embodiments the daily dosage of GLP-1 receptor
agonist is selected from the group consisting of 0.5 and 1.0
mg.
Oral Administration
[0070] The GLP-1 receptor agonist may be administered orally, for
example in the form of a tablet, a coated tablet, a sachet or a
capsule such as hard or soft gelatine capsule and all such
compositions are considered solid oral dosage forms. Oral
administration may be once daily administration. In some
embodiments the dosage of the GLP-1 receptor agonist is in the
range from 1 to 30 mg, such as 2 to 20 mg or 3 to 15 mg. In some
embodiments the dosage of GLP-1 receptor agonist is 3, 7 or 14 mg.
The composition may be in the form of a dose unit, such as tablet.
In some embodiments the weight of the unit dose is in the range of
50 mg to 1000 mg, such as in the range of 50-750 mg, or such as
about 100-500 mg. In some embodiments the weight of the dose unit
is in the range of 75 mg to 350 mg, such as in the range of 50-300
mg or 100-400 mg. The tablet for oral administration may comprise
30% (w/w) salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such
as the sodium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
(SNAC). In some embodiments the composition may be granulated prior
to being compressed to tablets. The composition may comprise a
granular part and/or an extra-granular part, wherein the granular
part has been granulated and the extra-granular part has been added
after granulation. The GLP-1 receptor agonist may be included in
the granular part or the extra-granular part. In some embodiments
the extra-granular part comprises the GLP-1 receptor agonist. In an
embodiment the extra-granular part may further comprise a lubricant
and/or a glidant. In an embodiment the granular part may comprise a
lubricant and/or a glidant. In an embodiment the granular part and
the extra-granular part comprise a lubricant and/or a glidant.
[0071] In some embodiments, the GLP-1 receptor agonist is the sole
pharmaceutically active ingredient administered according to the
present invention. In some embodiments, the GLP-1 receptor agonist
is combined with one or more further pharmaceutically active
ingredients in the present invention. In some embodiments, the
GLP-1 receptor agonist is combined with one or more further
pharmaceutically active ingredients selected from the group
consisting of rivastigmin, menantine (such as menantine
hydrochloride), donepezil and galantamine. In some embodiments, the
GLP-1 receptor agonist is combined with rivastigmin. In some
embodiments, the GLP-1 receptor agonist is combined with menantine,
such as menantine hydrochloride. In some embodiments, the GLP-1
receptor agonist is combined with donepezil. In some embodiments,
the GLP-1 receptor agonist is combined with galantamine.
[0072] In some embodiments the term "chronic treatment" as used
herein with reference to the GLP-1 receptor agonist means
administration in an amount and frequency to provide a therapeutic
effect. In some embodiments the term "chronic treatment" as used
herein with reference to GLP-1 receptor agonist means once weekly
administration of 0.1-3.0 mg, such as 0.5 or 1.0 mg, GLP-1 receptor
agonist (e.g. semaglutide). In some embodiments the term "chronic
treatment" as used herein with reference to a GLP-1 receptor
agonist means once daily administration of 0.05-0.3 mg, such as
0.05, 0.1, 0.2, or 0.3 mg, GLP-1 receptor agonist (e.g.
semaglutide). In some embodiments the term "chronic treatment" as
used herein with reference to a GLP-1 receptor agonist means once
daily administration of 0.1-6 mg, such as 0.5-4 mg, GLP-1 receptor
agonist (e.g. liraglutide). The term "chronic treatment" as used
herein may refer to administration of a drug according to a
prescribed dosage regimen (for example once weekly administration)
for a long period of time (for example at least 2 years or at least
5 years) wherein up to 10%, such as up to 5%, of dosages may be
missed; provided that no more than 10 consecutive dosages are
missed.
[0073] Unless otherwise stated, ranges herein include their end
points. In some embodiments the term "a" means "one or more". In
some embodiments, and unless otherwise indicated in the
specification, terms presented in singular form also include the
plural situation. Herein the term "about" means .+-.10% of the
value referred to, and includes the value.
Non-Limiting Embodiments of the invention
[0074] Non-limiting embodiments of the invention include: [0075] 1.
A method for the treatment of dementia, wherein said method
comprises administering a GLP-1 receptor agonist to a subject in
need thereof and said subject has metabolic syndrome. [0076] 2. A
method for the treatment of dementia, wherein said method comprises
administering semaglutide to a subject in need thereof. [0077] 3. A
method for reducing the risk of developing dementia, wherein said
method comprises administering a GLP-1 receptor agonist to a human
subject in need thereof and said subject has one or more
indications selected from the group consisting of pre-diabetes,
diabetes, cardiovascular disease, obesity, and hypertension. [0078]
4. A method for reducing the risk of developing dementia, wherein
said method comprises administering a GLP-1 receptor agonist to a
subject in need thereof and said subject has metabolic syndrome.
[0079] 5. A method for reducing the risk of developing dementia,
wherein said method comprises administering a GLP-1 receptor
agonist to a subject in need thereof and said subject has one or
more indications selected from the group consisting of
pre-diabetes, diabetes, cardiovascular disease, obesity, and
hypertension. [0080] 6. A method for reducing the risk of
developing dementia, wherein said method comprises administering
semaglutide to a subject in need thereof. [0081] 7. The method
according to any one of the preceding embodiments, wherein
treatment is reducing the risk of developing dementia. [0082] 8.
The method according to any one of the preceding embodiments,
wherein said metabolic syndrome is one or more indications selected
from the group consisting of pre-diabetes, diabetes, cardiovascular
disease, obesity, and hypertension. [0083] 9. The method according
to any one of the preceding embodiments, wherein said subject has
pre-diabetes. [0084] 10. The method according to any one of the
preceding embodiments, wherein said subject has diabetes. [0085]
11. The method according to any one of the preceding embodiments,
wherein said subject has cardiovascular disease. [0086] 12. The
method according to any one of the preceding embodiments, wherein
said subject has obesity. [0087] 13. The method according to any
one of the preceding embodiments, wherein said subject has
hypertension. [0088] 14. The method according to any one of the
preceding embodiments, wherein said GLP-1 receptor agonist
comprises GLP-1(7-37) (SEQ ID No: 1) optionally comprising one or
more substitutions, deletions, additions and/or modifications.
[0089] 15. The method according to any one of the preceding
embodiments, wherein said GLP-1 receptor agonist comprises a
maximum of 12 amino acids which have been altered, e.g., by
substitution, deletion, insertion and/or modification, compared to
GLP-1(7-37) (SEQ ID No: 1). [0090] 16. The method according to any
one of the preceding embodiments, wherein said GLP-1 receptor
agonist comprises a maximum of 10 amino acids which have been
altered, e.g., by substitution, deletion, insertion and/or
modification, compared to GLP-1(7-37) (SEQ ID No: 1). [0091] 17.
The method according to any one of the preceding embodiments,
wherein said GLP-1 receptor agonist comprises a maximum of 8 amino
acids which have been altered, e.g., by substitution, deletion,
insertion and/or modification, compared to GLP-1(7-37) (SEQ ID No:
1). [0092] 18. The method according to any one of the preceding
embodiments, wherein said GLP-1 receptor agonist comprises a
maximum of 6 amino acids which have been altered, e.g., by
substitution, deletion, insertion and/or modification, compared to
GLP-1(7-37) (SEQ ID No: 1). [0093] 19. The method according to any
one of the preceding embodiments, wherein said GLP-1 receptor
agonist comprises one or more substituents. [0094] 20. The method
according to any one of the preceding embodiments, wherein said
substituent comprises a linker, such as one or more OEG. [0095] 21.
The method according to any one of the preceding embodiments,
wherein said linker is located proximally in said substituent to
the point of attachment between said substituent and the peptide in
said GLP-1 receptor agonist. [0096] 22. The method according to any
one of the preceding embodiments, wherein said GLP-1 receptor
agonist has an EC50 (without HSA) of at most 500 pM. [0097] 23. The
method according to any one of the preceding embodiments, wherein
said GLP-1 receptor agonist is no more than 12 kDa. [0098] 24. The
method according to any one of the preceding embodiments, wherein
said GLP-1 receptor agonist is selected from the group consisting
of liraglutide, semaglutide, Compound A and Compound B. [0099] 25.
The method according to any one of the preceding embodiments,
wherein said GLP-1 receptor agonist is liraglutide. [0100] 26. The
method according to any one of the preceding embodiments, wherein
said GLP-1 receptor agonist is semaglutide. [0101] 27. The method
according to any one of the preceding embodiments, wherein said
GLP-1 receptor agonist is Compound A. [0102] 28. The method
according to any one of the preceding embodiments, wherein said
GLP-1 receptor agonist is Compound B. [0103] 29. The method
according to any one of the preceding embodiments, wherein said
GLP-1 receptor agonist is dulaglutide. [0104] 30. The method
according to any one of the preceding embodiments, wherein said
GLP-1 receptor agonist is albiglutide. [0105] 31. The method
according to any one of the preceding embodiments, wherein said
subject is human. [0106] 32. The method according to any one of the
preceding embodiments, wherein said dementia is all forms and all
stages in the dementia disease continuum. [0107] 33. The method
according to any one of the preceding embodiments, wherein said
dementia is mild cognitive impairment. [0108] 34. The method
according to any one of the preceding embodiments, wherein said
dementia is Alzheimer's disease. [0109] 35. The method according to
any one of the preceding embodiments, wherein said dementia is
selected from the group consisting of preclinical Alzheimer's
disease, mild cognitive impairment of the Alzheimer's type, early
onset familial Alzheimer's disease, and prodromal Alzheimer's
disease. [0110] 36. The method according to any one of the
preceding embodiments, wherein said dementia is preclinical
Alzheimer's disease. [0111] 37. The method according to any one of
the preceding embodiments, wherein said dementia is mild cognitive
impairment of the Alzheimer's type. [0112] 38. The method according
to any one of the preceding embodiments, wherein said dementia is
early onset familial Alzheimer's disease. [0113] 39. The method
according to any one of the preceding embodiments, wherein said
dementia is prodromal Alzheimer's disease. [0114] 40. The method
according to any one of the preceding embodiments, wherein said
GLP-1 receptor agonist is the sole pharmaceutically active
ingredient administered to said subject. [0115] 41. The method
according to any one of the preceding embodiments, wherein said
GLP-1 receptor agonist is administered subcutaneously. [0116] 42.
The method according to the preceding embodiment, wherein said
GLP-1 receptor agonist is administered in a composition which is in
the form of a solution or suspension. [0117] 43. The method
according to the preceding embodiment, wherein said composition
comprises at least 90% water. [0118] 44. The method according to
any one of the preceding embodiments, wherein said GLP-1 receptor
agonist is semaglutide, is administered subcutaneously, and is in
the form of a solution comprising at least 90% water and with pH in
the range of 7.0-9.0. [0119] 45. The method according to any one of
the preceding embodiments, wherein said GLP-1 receptor agonist is
administered orally. [0120] 46. The method according to the
preceding embodiment, wherein said GLP-1 receptor agonist is
administered in the form of a tablet. [0121] 47. The method
according to the preceding embodiment, wherein at least 30% (w/w)
of said tablet is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic
acid. [0122] 48. The method according to the preceding embodiment,
wherein at least 50% (w/w) of said tablet is a salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid. [0123] 49. The method
according to the preceding embodiment, wherein said salt of
N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC. [0124] 50. The
method according to any one of the preceding embodiments, wherein
said subject has previously been administered insulin. [0125] 51.
The method according to any one of the preceding embodiments,
wherein said method reduces the risk of mortality for said subject.
[0126] 52. The method according to any one of the preceding
embodiments, wherein said administration of a GLP-1 receptor
agonist is a chronic treatment in which semaglutide is administered
for at least 12 months, such as for at least 16 months or at least
18 months.
EXAMPLES
Example 1--Reduced Risk of Dementia in Subjects with Metabolic
Syndrome
Methods
[0127] Exposure to GLP-1 receptor agonist and subsequent diagnosis
of dementia was assessed in data sources with long term treatment
exposure including three pooled double-blind randomized controlled
trials (RCTs) and a nationwide cohort of patients with diabetes.
This was done with the aim of investigating whether use of GLP-1
receptor agonists reduces the onset of dementia in patients with
diabetes.
Trials and Registries
[0128] A triangulation approach integrating study designs and data
sources with different key sources of potential bias was employed
to obtain a more reliable answer. First, data was pooled from three
large RCTs with GLP-1 receptor agonists; liraglutide (LEADER; 9,340
patients), subcutaneous semaglutide (SUSTAIN-6; 3,297 patients),
and oral semaglutide (PIONEER 6; 3,183 patients). All three trials
were multicenter, double-blind, placebo-controlled cardiovascular
outcomes trials. Patients with type 2 diabetes at high risk for or
with established cardiovascular disease were randomly assigned in a
1:1 ratio, to receive placebo or liraglutide (LEADER), or
semaglutide (SUSTAIN-6; PIONEER 6) in addition to standard of care.
In these trials, the treatment for diabetes (excluding GLP-1
receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP4
inhibitors), and pramlintide) was adjusted or added in both arms,
at the investigator's discretion, as previously described. The
formulation tested in LEADER was an aqueous composition comprising
liraglutide, disodium phosphate dihydrate, propylene glycol, and
phenol at pH 8.15. The formulation tested in SUSTAIN-6 was an
aqueous composition comprising semaglutide, disodium phosphate
dihydrate, propylene glycol, and phenol at pH 7.4. The formulation
tested in PIONEER was a tablet comprising semaglutide and SNAC.
[0129] Next, we used the Danish National Prescription Register,
which holds information on all redeemed prescriptions in Denmark
since Jan. 1, 1995 (Table S1), to identify a nationwide cohort of
patients treated for diabetes. We identified everyone with a first
prescription of a second line diabetes treatment (Table S2) between
Jan. 1, 1995 and Dec. 31, 2017.
[0130] Follow-up for onset of dementia started on Jan. 1, 2009
(FIG. 4), as this was when GLP-1 receptor agonists could be
considered a well-known and available treatment for diabetes in
Denmark. To correctly identify patients with a first ever
prescription for a second line diabetes treatment, we excluded
those who had a prescription between Jan. 1, 1995 through Jun. 30,
1995. Furthermore, patients with established dementia before start
of follow-up or who developed dementia before age 50 were
excluded.
[0131] For the main analysis we included everyone with at least 5
years of exposure to second line diabetes treatment.
Exposure to GLP-1 Receptor Agonists
[0132] The predefined treatment durations for the 3 RCTs are listed
in Supplementary Table S4. In the nationwide cohort, all dispensed
prescriptions for GLP-1 receptor agonists were identified (Table
S2), and years of cumulative GLP-1 receptor agonist exposure were
updated throughout the follow-up period. Patients were considered
exposed if they had redeemed at least 1 prescription for any GLP-1
receptor agonists. The exposure duration was accumulated according
to 6 months long intervals, in which at least 1 prescription was
redeemed.
Exposure to other Diabetes Treatments
[0133] In the nationwide cohort, "other second line diabetes
treatments" were assessed to test whether or not a potential
influence of GLP-1 receptor agonists on dementia prevention was
specific for treatment with GLP-1 receptor agonists. We identified
other second line diabetes treatment that were available as
alternative treatment options to GLP-1 receptor agonists during the
follow-up period, i.e. insulin, sulfonylureas, DPP4 inhibitors,
acarbose, and meglitinides (Table S2). Exposure time was
accumulated according to six months long intervals, in which at
least 1 prescription was redeemed. Monotherapy with metformin was
not assessed, since this is considered first-line treatment for
diabetes and thus not a comparable treatment option to GLP-1
receptor agonists.
Dementia
[0134] In the RCTs, the Standardized Medical Dictionary for
Regulatory Activities (MedDRA, version 21.1) was used to identify
dementia-related adverse events using the narrow scope search terms
for dementia (Table S3). In the nationwide cohort, dementia was
defined as a diagnosis of dementia in the National Patient Register
or first ever prescription for approved dementia specific treatment
in the National Prescription Register (cholinesterase inhibitors
and memantine) (Table S1 and S2 lists the ICD10 and ATC codes).
Statistical Analysis
[0135] For the pooled RCTs, an intention-to-treat analysis was
performed using Cox regression with treatment assignment as the
only explanatory variable to determine the hazard ratio for
developing dementia with GLP-1 receptor agonists versus placebo. We
reported the hazard ratio for dementia for patients randomized to a
GLP-1 receptor agonist versus placebo. The incidence of dementia
with death as competing risk was calculated using the
Aalen-Johansen estimator.
[0136] In the nationwide cohort we employed a nested case-control
study design where each patient at case date (date of dementia
diagnosis) was matched on age, sex and calendar date to 10 controls
without dementia. The effects of differences in cumulative exposure
to GLP-1 receptor agonists for developing dementia were modelled
with Cox regression in a 5 year exposure window prior to case date
(FIG. 4) and reported as hazard ratios for each 1 year increase in
GLP-1 receptor agonist exposure for cases versus controls. Reported
were hazard ratios for each 1 year increase in duration of. The
model was adjusted for age, sex, and calendar date via matching,
and information on diabetes duration (years since first ever
prescription of any second line diabetes treatment), stroke,
myocardial infarction, hypertension, chronic renal disease, and
educational attainment (Table S1 and S2) at the start of the
exposure window. A similar Cox regression model was employed for
each of the other second line diabetes treatments. Furthermore, the
hazard ratio for dementia with exposure to GLP-1 receptor agonists
was investigated across subgroups, including sex, age, insulin
exposure, and cardiovascular status, where cardiovascular disease
was defined as prior stroke or myocardial infarction. In the
nationwide cohort, prespecified sensitivity analyses were performed
to determine the effect of 1) reverse causation, where exposure two
years before the case date was ignored; 2) diabetes duration
defined as "time since first treatment with metformin or second
line diabetes treatment; 3) shortening and lengthening the exposure
windows (3- and 10-years, respectively); 4) adjustment only via
matching on age, sex, and calendar date and 5) competing risk of
death. The level of statistical significance was set at 5%.
Results
Study Populations
[0137] In total, 15,820 patients at high risk for or with
established cardiovascular disease were randomized to a GLP-1
receptor agonist or placebo in the pooled RCTs. Baseline
characteristics are presented in Table 1.
[0138] In the nationwide cohort of 120,054 patients with at least 5
years since initiation of a second line diabetes treatments, 4,849
patients developed dementia during the follow-up period from 2009
through 2017. Characteristics of case and control patients are
presented in Table 2. Liraglutide comprised 95% of all
prescriptions for GLP-1 receptor agonists.
Dementia in Pooled RCTs
[0139] In the pooled RCTs, 15 patients randomized to a GLP-1
receptor agonist and 32 patients randomized to placebo developed
dementia during a median follow-up of 3.61 years (Table S4).
[0140] Patients randomized to GLP-1 receptor agonists had a lower
risk of developing dementia compared to those randomized to placebo
(hazard ratio 0.47; 95% confidence interval (CI), 0.25 to 0.86)
(FIG. 1 and Table S5). The beneficial effects of GLP-1 receptor
agonists became apparent after 12 months of treatment (FIG. 1).
Dementia in the Nationwide Cohort
[0141] The median follow-up time in the nationwide cohort was 7.4
years. The analysis nested in the nationwide cohort was
specifically designed to examine long term effects by ensuring at
least 5 years of treatment with second line diabetes therapy. The
result was a reduction of hazard of dementia with increasing
duration of GLP-1 receptor agonist exposure (FIG. 2). Exposure to
other second line diabetes treatments was not found to be
associated with a decrease in hazard ratio (FIG. 2). The reduction
in hazard ratio for dementia with exposure to GLP-1 receptor
agonists was similar across subgroups stratified by sex, age,
co-exposure to insulin, and cardiovascular status (FIG. 3).
[0142] The results were not changed by excluding exposure in the
two years leading up to the diagnosis of dementia (FIG. 5A), and
when diabetes duration was assessed as "time since first treatment
with metformin or second line diabetes treatment", although an
association with DDP4 inhibitors was found to be protective against
dementia (FIG. 5B). Furthermore, the results for dementia remained
unchanged when exposure to GLP-1 receptor agonists was assessed
within 3 and 10 years before diagnosis of dementia (FIG. 6A).
Adjusting for only age, sex, and calendar date via matching also
yielded the same results (FIG. 6B). Lastly, the analysis of death
as competing risk, which assessed the hazard ratio for death
without a previous dementia diagnosis, showed a lower hazard ratio
for death with exposure to GLP-1 receptor agonists (FIG. 6C).
[0143] In conclusion, it was found that treatment with GLP-1
receptor agonists was associated with a reduced risk of dementia in
patients with diabetes.
TABLE-US-00001 TABLE 1 Baseline Characteristics in the Pooled RCTs
GLP-1 Receptor Agonist Placebo Characteristics (N = 7,907) (N =
7,913) Male sex - no. (%) 5108 (64.6) 5073 (64.1) Age - no. (%)
64.6 (7.2) 64.8 (7.3) <70 5942 (75.2) 5850 (73.9) 70-80 1764
(22.3) 1864 (23.6) 80-90 198 (2.5) 198 (2.5) >90 3 (0.4) 1
(0.01) Diabetes duration - mean (.+-.SD) 13.5 (8.2) 13.5 (8.2)
Stroke - no. (%) 1229 (15.5) 1299 (16.4) Myocardial infarction -
no. (%) 2554 (32.3) 2531 (32.0) Hypertension - no. (%)* 5804 (91.9)
5766 (91.2) Chronic renal disease - no. (%).sup..dagger. 189 (2.4)
173 (2.2) *Not including the PIONEER 6 trial. .sup..dagger.Chronic
renal disease is defined as eGFR < 30.
TABLE-US-00002 TABLE 2 Characteristics of the Case and Control
Patients in the Nationwide Cohort Cases Controls Characteristics (N
= 4,849) (N = 48,506) Male sex - no. (%) 2299 (47.4) 22998 (47.4)
Age - no (%) <70 1278 (26.4) 12784 (26.4) 70-80 2268 (46.8)
22688 (46.8) 80-90 1260 (26.0) 12612 (26.0) >90 43 (0.9) 422
(0.9) Diabetes duration - mean (.+-.SD)*.sup..dagger. 6.6 (4.1) 6.4
(4.1) GLP-1 receptor agonists - no. (%) 0 years 4575 (94.3) 44594
(91.9) 1-2 years 59 (1.2) 623 (1.3) 2-3 years 35 (0.7) 586 (1.2)
3-4 years 35 (0.7) 483 (1.0) 4-5 years 74 (1.5) 1076 (2.2) Stroke -
no. (%) 760 (15.7) 5628 (11.6) Myocardial infarction - no. (%) 527
(10.9) 5241 (10.8) Hypertension - no. (%)* 3252 (67.1) 31961 (65.9)
Chronic renal disease - no. (%).sup..dagger. 233 (4.8) 2287 (4.7)
Educational attainment - no. (%).sup..dagger-dbl. Basic 2490 (51.4)
23920 (49.3) Medium 1508 (31.1) 14971 (30.9) Advanced 427 (8.8)
4681 (9.7) *Time since initiation of second-line diabetes
treatment. .sup..dagger.At beginning of 5-year exposure window,
.sup..dagger-dbl.In patients who received GLP-1 receptor agonists.
.intg. Educational status unknown in 424 (8.7%) cases and in 4934
(10.2%) controls.
TABLE-US-00003 TABLE S1 Data Sources. Registers/databases/ Data
Source Clinical Trial information Variables Pooled RCTs LEADER
ClinicalTrials.gov number, Liraglutide versus placebo NCT01179048.
Multicenter, double-blind, placebo-controlled trial conducted at
410 sites in 32 countries SUSTAIN-6 ClinicalTrials.gov number,
Subcutaneous semaglutide NCT01720446. versus placebo Multicenter,
double-blind, placebo-controlled trial conducted at 230 sites in 20
countries PIONEER 6 ClinicalTrials.gov number, Oral semaglutide
versus placebo NCT02692716 Multicenter, double-blind, Nationwide
The Danish Diagnosis of: cohort National Patient Register Dementia,
hypertension, myocardial infarction, stroke, and chronic renal
disease The Danish register of Medicinal Treatment for: Product
Statistics Dementia, diabetes, and hypertension Danish Register of
Causes of Vital status, causes of death Death Population Education
Register Educational attainment
TABLE-US-00004 TABLE S2 Overview of Definitions of Diabetes
Treatments, Dementia, and Comorbidities for the Nationwide Cohort.
Condition/treatment ATC codes and ICD codes Diabetes treatments
(ATC codes) Metformin A10BA02 GLP-1 receptor agonists A10BJ Insulin
A10A Acarbose A10BF DPP4 inhibitors A10BH Sulfonylureas A10BB
Meglitinides A10BX TZD* A10BG SGLT-2i* A10BK Dementia** (ATC codes)
Donepezil N06DA02 Rivastigmine N06DA03 Galantamine N06DA04
Memantine N06DX01 (ICD codes) DF00, DG30, DF01, DF023, DF028, DF03
Comorbidities (ICD codes) Hypertension ICD-10: DI10-DI13, DI15 ATC:
C02-C03, C07, C09 Myocardial infarction ICD-8: 410 ICD-10: DI21,
DI22 Stroke ICD-8: 433-438 ICD-10: DI63, DI64, DG458, DG459 Chronic
renal disease ICD-8: 25002, 40039, 59009, 59320, 75310-75311, 75319
ICD-10: DN158-DN159, DQ612-DQ613, DQ615, DG619, DE102, DE112 DE132,
DE142, DI120, DN160, DN162- DN164, DN168, DM300, DM313, DM319,
DM321B *These products were not available at the same calendar
period as GLP-1 receptor agonists and thus were not considered
alternative treatment options to GLP-1 receptor agonists. *The last
6 months of 2017, dementia was only defined by dementia treatments
due to register availability.
TABLE-US-00005 TABLE S3 Dementia (Narrow Scope) Standardized MedDRA
Queries (SMQs) Search Terms* Applied in the Post Hoc Analysis of
the Pooled RCTs. Name Scope Clinical dementia rating scale score
abnormal Narrow Corticobasal degeneration Narrow Creutzfeldt-Jakob
disease Narrow Dementia Narrow Dementia Alzheimer's type Narrow
Dementia of the Alzheimer's type, uncomplicated Narrow Dementia of
the Alzheimer's type, with delirium Narrow Dementia of the
Alzheimer's type, with delusions Narrow Dementia of the Alzheimer's
type, with depressed mood Narrow Dementia with Lewy bodies Narrow
Early onset familial Alzheimer's disease Narrow Frontotemporal
dementia Narrow Hippocampal sclerosis Narrow Korsakoff's syndrome
Narrow Mini mental status examination abnormal Narrow Mixed
dementia Narrow Presenile dementia Narrow Prion disease Narrow
Progressive supranuclear palsy Narrow Scatolia Narrow Senile
dementia Narrow Variant Creutzfeldt-Jakob disease Narrow Vascular
dementia Narrow *version 21.1
TABLE-US-00006 TABLE S4 Prespecified Sensitivity Analyses in the
Nationwide Cohort. Sensitivity Analyses 1) Reverse causation, where
exposure two years before the case date was ignored 2) Diabetes
duration defined as "time since first treatment with metformin or
second line diabetes treatment 3) Shortening and lengthening the
exposure windows (3- and 10-years, respectively) 4) Adjustment only
via matching on age, sex, and calendar date 5) Competing risk of
death
TABLE-US-00007 TABLE S5 Median Follow-up and Rates of Dementia in
each of the Included RCTs. Dementia SMQ GLP-1 Receptor Dementia SMQ
Median Agonists Placebo Treatment Follow-up no. of no. of RCT
Groups Duration events rate events rate LEADER* Liraglutide 3.8
years 12 0.69 25 1.45 EX2211-3748 vs. placebo SUSTAIN-6.dagger.
Semaglutide (s.c) 2.1 years 3 0.88 5 1.47 NN9535-3744 vs. placebo
PIONEER 6.dagger-dbl. Semaglutide (oral) 1.3 years 0 2 0.96
NN9924-4221 vs. placebo *In LEADER, the minimum planned follow-up
was 42 months, with a maximum of 60 months of receiving the
assigned regimen and subsequently 30 days of follow-up. .dagger.In
SUSTAIN-6 the planned observation period was 109 weeks, consisting
of 104 weeks of the assigned regimen and subsequently 5 weeks of
follow-up. .dagger-dbl.In PIONEER 6, no predefined minimum
treatment duration was required, but follow-up was required to
continue until 122 events of the primary outcome had occurred.
TABLE-US-00008 TABLE S6 Hazard Ratio for Dementia in the Pooled
RCTs according to Dementia Subtypes. GLP-1 Receptor Agonist Placebo
Hazard Ratio for Diagnoses no. of patients no. of patients Dementia
(95% CI) Dementia 6 15 Dementia Alzheimer's 5 7 type Dementia with
Lewy 0 2 bodies Mixed dementia 2 2 Senile dementia 1 3 Vascular
dementia 1 3 Total 15 (0.19%) 32 (0.40%) 0.47 (0.25-0.86)
Example 2--Semaglutide Prevents Cognitive Decline in the Senescence
Accelerated Prone 8 (SAMP8) Mouse
[0144] The inbred senescence-accelerated mouse-prone 8 (SAMP8)
model is a non-transgenic mouse line that displays phenotypes
associated with sporadic (not driven by a defined genetic cause)
Alzheimer's dementia, including measurable cognitive decline. SAMP8
mice display accelerated ageing and thus also model age-related
metabolic complications, showing increased markers of oxidative
stress and inflammation. As cognitive deficits can be measured in
this model prior to the presence of overt neuropathology such as
the accumulation of amyloid plaques in the brain, this mouse model
allows for the assessment of drug effects on preventing cognitive
decline and models early stages of disease in humans.
[0145] Here, SAMP8 mice were utilized to characterize the impact of
semaglutide treatment on memory deficits and cognitive decline. Two
behavioural tests commonly used to assess cognitive deficits in
rodents were employed to assay effects on short-term memory (Y-maze
test) and long-term memory (step-through passive avoidance test).
The Y-maze is test of short-term memory, assessing spatial working
memory and exploratory behaviour by measuring spontaneous
alternations, which is the frequency of entering a new arm of the
maze rather than returning to one that was previously visited
(described in methods). The step-through passive avoidance test
measures associative long-term memory by assessing the learning of
an association of an aversive stimulus to a particular context
(described in methods). SAMP8 mice have measurable deficits in both
tests as they age.
Methods
[0146] The experiment was carried out using SAMP8 mice with the
following treatment groups: SAMP8 vehicle treated (n=24) and SAMP8
semaglutide (30 nmol/kg) treated (n=11). Treatment was commenced at
six weeks of age. Treatment was delivered subcutaneously once a
day, with an initial titration period of for semaglutide of 3
nmol/kg on the first day of dosing, 10 nmol/kg on the second day of
dosing and proceeding with 30 nmol/kg thereafter.
[0147] Testing in the Y-maze was performed at 8 weeks of age and 16
weeks of age, at approximately 15 and 71 days following treatment
initiation respectively. The Y-maze was comprised of grey
polyvinylchloride with three arms 40 cm long, 13 cm high, 3 cm wide
at the bottom, 10 cm wide at the top converging at an equal angle.
Each mouse was placed at the end of one arm and allowed to move
freely through the maze during an eight minute session. The series
of arm entries including possible returns into the same arm was
monitored and alternation was defined as entries into all three
arms on consecutive occasions. The number of maximum alternations
was therefore the total number of arm entries minus two and the
percentage of alternation was be calculated as (actual
alternations/maximum alternations).times.100.
[0148] The step through passive avoidance performance was performed
at 18 weeks of age. Testing was performed in an apparatus
comprising of a two-compartment box (15.times.20.times.15 cm high)
where one compartment was illuminated with white polyvinylchloride
walls and the other was darkened with black polyvinylchloride walls
and a grid floor. A guillotine door separated the compartments. A
60 W lamp positioned 40 cm above the apparatus illuminated the
white compartment during the experiment. Scrambled footshocks (0.3
mA for 3 s) could be delivered to the grid floor using a shock
generator scrambler (Lafayette Instruments, Lafayette, USA). A
training session was first performed where the guillotine door was
initially closed and each mouse was placed into the white
compartment. After 5 s, the door was raised. When the mouse entered
the darkened compartment and placed all four paws on the grid
floor, the door was closed and the footshock delivered for 3 s to
associate the darkened chamber with a footshock. A retention test
was carried out 24 h after training. Each mouse was again placed
into the white compartment and after 5 s, the door was raised. The
step-through latency was recorded up to 300 s, defined as the time
it took the mouse to enter the darkened compartment during the
retention test. Escape latency was as recorded, defined as the time
in the retention test to escape the darkened chamber following the
application of a footshock.
Results
[0149] Data in FIG. 7 illustrates that vehicle-treated SAMP8 mice
had, as expected, significantly decreased percentage alternation
behaviour in the Y-maze at 16 weeks (mean.+-.SEM: 42.8%.+-.2.1%)
versus 8 weeks (mean.+-.SEM: 69.1%.+-.1.3%) of age (p<0.0001,
2-way ANOVA, Sidak's multiple comparison test). Semaglutide-treated
SAMP8 mice at 16 weeks of age had significantly improved
alternation behaviour (mean.+-.SEM: 79.1%.+-.1.6%) compared to
vehicle-treated SAMP8 (mean.+-.SEM: 42.8%.+-.2.1%) controls
(p<0.0001, 2-way ANOVA, Sidak's multiple comparison test). These
data show semaglutide has a positive effect on preserving short
term memory function in SAMP8 mice as measured in the Y maze
test.
[0150] Semaglutide also improved long-term memory in SAMP8 mice as
measured in the step-through passive avoidance test (FIG. 8-9).
Semaglutide-treated SAMP8 mice had significantly increased
step-through latency into the darkened chamber during the retention
phase, which was previously associated with a footshock (FIG. 8;
SAMP8 vehicle-treated mean.+-.SEM: 109.8 seconds .+-.5.8 seconds;
SAMP8 semaglutide-treated mean.+-.SEM: 260.5 seconds .+-.14.5
seconds, p<0.0001, Mann-Whitney test). Semaglutide-treated SAMP8
mice also had significantly lower escape latency from the darkened
chamber (FIG. 9; SAMP8 vehicle treated mean.+-.SEM: 88.8 seconds
.+-.4.6 seconds; SAMP8 semaglutide-treated mean.+-.SEM: 19.0
seconds .+-.3.0 seconds, p=0.01, unpaired t test).
[0151] Semaglutide treatment did not result in differences in body
weight (16 weeks of age; SAMP8 vehicle-treated mean.+-.SEM: 31.0
grams .+-.0.43 grams or 148.0%.+-.4.6% change in body weight from
baseline; SAMP8 semaglutide-treated mean.+-.SEM: 29.2 grams .+-.0.7
grams or 145.4%.+-.4.2% change in body weight from baseline) or
blood glucose (SAMP8 vehicle-treated mean.+-.SEM: 137.1 mg/dL
.+-.5.6 mg/dL; SAMP8 semaglutide-treated mean.+-.SEM: 133.1 mg/dL
.+-.2.2 mg/dL) compared to vehicle treated animals.
CONCLUSION
[0152] Chronic semaglutide treatment prevented cognitive decline in
SAMP8 mice. Semaglutide prevented decline in alternation behaviour
in the Y-maze, indicating improved short-term and spatial memory
compared to vehicle-treated SAMP8 controls. Semaglutide also
prolonged the step-through latency and shortened the escape latency
in the step-through passive avoidance test, which are positive
indicators of longer-term memory performance and associative
learning. These positive effects on cognitive parameters
furthermore appear to be a novel effect of semaglutide that is not
driven by changes in glycaemia or body weight. Example 2
surprisingly shows better effects of semaglutide than those
published for liraglutide in the same animal model.
Example 3--Semaglutide Reduces Brain Inflammation
(Neuroinflammation) in a Lipopolysaccharide (LPS) Inflammation
Mouse Model
[0153] Neuroinflammation is part of the pathology comprising
dementia and Alzheimer's disease, with human brain imaging studies
highlighting increased markers of inflammation in Alzheimer's
disease (e.g. translocator protein 18 kDa levels) and genetic
association studies in humans highlighting that genes associated
with Alzheimer's disease are part of inflammatory pathways.
Inflammation is also linked to metabolic disease in humans
(obesity, type 2 diabetes, cardiovascular diseases) and thus could
affect progression of cognitive decline and dementia in people with
metabolic diseases.
[0154] LPS-induced neuroinflammation is used as a non-genetic model
of Alzheimer's disease in rodents. LPS is an endotoxin from
gram-negative bacteria that provides a persistent inflammatory
stimulus activating brain immune cells (neuroimmune cells).
Microglia are a brain immune cell type activated by LPS, and the
degree of neuroinflammation can be assessed by the area of
microglia in brain tissue as measured by the microglia-specific
marker ionized calcium binding adaptor molecule 1 (Iba1).
[0155] Here, LPS-induced neuroinflammation in mice was used to
assess the impact of semaglutide on attenuating brain inflammation
in the hippocampus, a brain region involved in memory and learning
which is deteriorated in Alzheimer's Disease.
Methods
[0156] The experiment was carried out using C57BL/6 mice at 8-10
weeks of age. Mice were treated with semaglutide (30 nmol/kg,
subcutaneously once per day) or vehicle from Day 1 to Day 28 of the
study. To induce inflammation, LPS was administered (1.0 mg/kg,
intraperitoneally once per day) for three days at days 15-17 of the
study, with control animals receiving vehicle. Induction of
inflammatory cytokines was verified by measuring plasma tumor
necrosis factor alpha levels on Day 15, one hour after LPS dosing.
Animals were terminated at either Day 19 (Day 2 after LPS
treatment) or Day 28 (Day 11 after LPS treatment) for to measure
markers of neuroinflammation. All treatment groups had n=8-12.
[0157] Immediately after termination, whole brains were collected
for immunohistochemical (IHC) analyses of neuroinflammation
markers. Brains were immersion fixated in 10% neutral buffered
formalin for approximately 48 h and then transferred to 70% ethanol
and stored at 4.degree. C. until paraffin embedding in blocks.
Serial sections representing the rostro-caudal axis of the dorsal
hippocampus were cut at 4 .mu.m and collected on Superfrost plus
slides. Paraffin embedded sections were de-paraffinated in xylene
and rehydrated in series of graded ethanol. IHC for Iba1 was
performed using Iba1 primary antibody (Abcam, Cat. Ab178845).
Following antigen retrieval and blocking of endogenous peroxidase
activity, slides were incubated with primary antibody. The primary
antibody was detected using a linker secondary antibody followed by
amplification using a polymeric HRP-linker antibody conjugate.
Next, the primary antibody was visualized with DAB as chromogen and
counterstained in hematoxylin.
[0158] Quantitative assessment of Iba1 signal was performed to
measure the area of microglia in the hippocampus of the tissue
section. Assessment was performed using a two-step protocol with
VIS (Visiopharm, Denmark) software. First, crude detection of
tissue at low magnification (1.times. objective) and delineation of
the Region of Interest (ROI) was obtained. Second, detection of
IHC-positive staining was performed at higher magnification
(10.times. objective) inside the ROI. The quantitative estimates of
IHC-positive staining were calculated as an area fraction (AF) of
the total tissue area where:
A .times. F IHC - positive .times. signal = A .times. r .times. e
.times. a IHC - positive .times. signal A .times. r .times. e
.times. a IHC - positive .times. signal + A .times. r .times. e
.times. a tissue ##EQU00001##
Results
[0159] Semaglutide lowered the microglial inflammatory marker Iba1
in the hippocampus following LPS administration. Results in FIG. 10
show that LPS significantly increased hippocampal Iba1 area on Day
19 in mice dosed with LPS+ vehicle compared to vehicle/vehicle
dosed controls (p<0.001, Dunnett's test one-factor linear model;
Day 19 vehicle/vehicle mean.+-.SEM: 8.98%.+-.0.34%, Day 19 LPS+
vehicle mean.+-.SEM: 14.25%.+-.0.54%) illustrating that
neuroinflammation was induced by LPS. On Day 28, while LPS+ vehicle
treated mice continued to have a significantly higher area of
hippocampal Iba1 (p<0.05 vs vehicle/vehicle controls, Dunnett's
test one-factor linear model; Day 28 vehicle/vehicle mean.+-.SEM:
9.77%.+-.0.54%, Day 28 LPS+ vehicle mean.+-.SEM: 12.17%.+-.0.88%),
semaglutide treatment significantly reduced Iba1 area in LPS+
semaglutide-treated mice (p<0.01 vs LPS+ vehicle treated mice,
Dunnett's test one-factor linear model; Day 28 LPS+ vehicle
mean.+-.SEM: 12.17%.+-.0.88%, Day 28 LPS+ semaglutide mean.+-.SEM:
8.53%.+-.0.49%).
[0160] There was no meaningful difference in body weight at Day 28
between mice dosed with LPS+ vehicle (mean.+-.SEM: 23.83 g.+-.0.33
g) versus those treated with LPS+ semaglutide (mean.+-.SEM:
22.98g.+-.0.70g).
CONCLUSION
[0161] In an LPS-induced neuroinflammation model, semaglutide
reduced neuroinflammation in both the hippocampus as measured by
the area of microglia (Iba1). Semaglutide treatment reduced
neuroinflammation implicating that this may be a novel mechanism
through with semaglutide may have effects on cognition.
[0162] While certain features of the invention have been
illustrated and described herein, many modifications,
substitutions, changes, and equivalents will now occur to those of
ordinary skill in the art. It is, therefore, to be understood that
the appended claims are intended to cover all such modifications
and changes as fall within the true spirit of the invention.
Sequence CWU 1
1
1131PRTHomo sapiens 1His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser
Ser Tyr Leu Glu Gly1 5 10 15Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu
Val Lys Gly Arg Gly 20 25 30
* * * * *