U.S. patent application number 16/068255 was filed with the patent office on 2019-02-28 for tesofensine and metoprolol for treatment of hypertension.
This patent application is currently assigned to Saniona A/S. The applicant listed for this patent is SANIONA A/S. Invention is credited to Berit EDSBERG, Thomas Amos JACOBSEN.
Application Number | 20190060301 16/068255 |
Document ID | / |
Family ID | 57909413 |
Filed Date | 2019-02-28 |
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United States Patent
Application |
20190060301 |
Kind Code |
A1 |
EDSBERG; Berit ; et
al. |
February 28, 2019 |
TESOFENSINE AND METOPROLOL FOR TREATMENT OF HYPERTENSION
Abstract
The present invention relates to treatment of hypertension using
a combination of tesofensine and metoprolol. The treatment is
particularly well suited for the treatment of hypertensive obese
subjects and hypertensive diabetic subjects.
Inventors: |
EDSBERG; Berit; (Kongens
Lyngby, DK) ; JACOBSEN; Thomas Amos; (Olsted,
DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANIONA A/S |
Ballerup |
|
DK |
|
|
Assignee: |
Saniona A/S
Ballerup
DK
|
Family ID: |
57909413 |
Appl. No.: |
16/068255 |
Filed: |
December 30, 2016 |
PCT Filed: |
December 30, 2016 |
PCT NO: |
PCT/DK2016/050477 |
371 Date: |
July 5, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/138 20130101;
A61K 31/46 20130101; A61P 9/12 20180101; A61K 31/46 20130101; A61K
2300/00 20130101; A61K 31/138 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/46 20060101
A61K031/46; A61K 31/138 20060101 A61K031/138; A61P 9/12 20060101
A61P009/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 15, 2016 |
DK |
PA 2016 70018 |
Claims
1. A method for treating hypertension or pre-hypertension in a
hypertensive or pre-hypertensive subject, comprising administering
to said subject: i) 0.1 mg to 1 mg of tesofensine or a
pharmaceutically acceptable salt thereof; ii) 10 mg to 200 mg of
metoprolol or a pharmaceutically acceptable salt thereof.
2. (canceled)
3. The method according to claim 1, wherein the subject is
suffering from pre-hypertension, stage 1 hypertension, stage 2
hypertension or isolated systolic hypertension, prior to the
administration.
4. The method according to claim 1, wherein the subject has a
systolic blood pressure in the range of 120-139 mmHg and a
diastolic blood pressure in the range of 80-89 mmHg, prior to the
administration.
5. The method according to claim 1, wherein the subject has a
systolic blood pressure above 135 mmHg and/or a diastolic blood
pressure above 85 mmHg, prior to the administration.
6. The method according to claim 1, wherein the subject has a
systolic blood pressure above 140 mmHg and/or a diastolic blood
pressure above 90 mmHg, prior to the administration.
7. The method according to claim 1, wherein the subject has a
systolic blood pressure in the range of 140-159 mmHg and a
diastolic blood pressure in the range of 90-99 mmHg, prior to the
administration.
8. The method according to claim 1, wherein the subject has a
systolic blood pressure in the range of 160-179 mmHg and a
diastolic blood pressure in the range of 100-109 mmHg, prior to the
administration.
9. The method according to claim 1, wherein the subject has a
systolic blood pressure at or above 140 mmHg and a diastolic blood
pressure below 90 mmHg, prior to the administration.
10. The method according to claim 1, wherein the subject is a child
or an adolescent having an average systolic blood pressure (SBP) or
diastolic blood pressure (DBP) that is .gtoreq.95th percentile for
gender, age, and height on at least 3 separate occasions or wherein
the subject has an average SBP or DBP levels that are .gtoreq.90th
percentile but <95th percentile, prior to the
administration.
11. The method according to claim 1, wherein the subject is obese,
prior to the administration.
12. The method according to claim 1, wherein the subject has a BMI
above 25 kg/m.sup.2.
13. The method according to claim 12, wherein the subject has a BMI
above 30 kg/m.sup.2.
14. The method according to claim 1, wherein the subject is
suffering from diabetes, prior to the administration.
15. The method according to claim 14, wherein the diabetes is type
1 diabetes, type 2 diabetes, pre-diabetes, or gestational
diabetes.
16. The method according to claim 14, wherein the subject is
suffering from type 1 diabetes, prior to the administration.
17. The method according to claim 14, wherein the subject is
suffering from type 2 diabetes, prior to the administration.
18. The method according to claim 14, wherein the subject is
suffering from pre-diabetes, prior to the administration.
19. The method according to claim 14, wherein the subject is
suffering from gestational diabetes, prior to the
administration.
20. The method according to claim 1, wherein the subject is further
suffering from a disorder or condition that is metabolic syndrome,
dyslipidemia, atherosclerosis, drug-induced obesity, an overeating
disorder, bulimia nervosa, binge eating disorder, compulsive
over-eating, impaired appetite regulation, Prader Willi Syndrome
(PWS), nonalcoholic fatty liver disease (NAFLD), or nonalcoholic
steatohepatitis (NASH) prior to the administration.
21. The method according to claim 1, wherein the subject is a
human.
22. The method according to claim 1, wherein the administration
results in a decrease in the systolic blood pressure of the subject
and/or a decrease in the diastolic blood pressure of the subject,
as compared to prior to the administration.
23. The method according to claim 1, wherein the administration
results in a decrease in the systolic blood pressure by at least 5
mm Hg, as compared to the subject's systolic blood pressure prior
to the administration.
24. The method according to claim 1, wherein the administration
results in a decrease in the systolic blood pressure by at least
5%, as compared to the subject's systolic blood pressure prior to
the administration.
25. The method according to claim 1, wherein the administration
results in a decrease in the diastolic blood pressure by at least 5
mm Hg, as compared to the subject's diastolic blood pressure prior
to the administration.
26. The method according to claim 1, wherein the administration
results in a decrease in the diastolic blood pressure by at least
5%, as compared to the subject's diastolic blood pressure prior to
the administration.
27. The method according to claim 1, wherein the tesofensine or a
pharmaceutically acceptable salt thereof and the metoprolol or a
pharmaceutically acceptable salt thereof are administered
orally.
28. The method according to claim 1, wherein the tesofensine or a
pharmaceutically acceptable salt thereof and the metoprolol or a
pharmaceutically acceptable salt thereof are administered
simultaneously, sequentially or separately.
29. The method according claim 1, wherein the tesofensine or a
pharmaceutically acceptable salt thereof and the metoprolol or a
pharmaceutically acceptable salt thereof are co-administered as a
single pharmaceutical composition.
30. The method according to claim 1, wherein the metoprolol or a
pharmaceutically acceptable salt thereof are administered as a
pharmaceutical composition having an extended release profile.
31. The method according to claim 1, wherein the tesofensine or a
pharmaceutically acceptable salt thereof is administered to said
subject at a dose of 0.25 mg to 0.75 mg of tesofensine per day.
32. The method according to claim 1, wherein the metoprolol or a
pharmaceutically acceptable salt thereof is administered to said
subject at a dose of 25-100 mg of metoprolol per day.
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. (canceled)
42. (canceled)
43. (canceled)
44. The method according to claim 1, wherein the administration
results in reduction of the subject's BMI, as compared to prior to
the administration.
45. The method according to claim 14, wherein the administration
results in alleviation of the diabetes.
46. The method according to claim 14, wherein the administration
results in alleviation of diabetic complications in the
subject.
47. The method according to claim 20, wherein the subject is
suffering from a fatty liver disorder and wherein the
administration results in reduction of the fatty liver disorder, as
compared to prior to the administration.
Description
FIELD OF INVENTION
[0001] The present invention relates to the treatment of
hypertension using a combination of tesofensine and metoprolol,
particularly to the treatment of hypertensive obese subjects and
hypertensive diabetic subjects.
BACKGROUND OF INVENTION
[0002] Hypertension, i.e. high blood pressure, is a chronic medical
condition in which the blood pressure in the arteries is
persistently elevated. Sustained hypertension over time is a major
risk factor for hypertensive heart disease, coronary artery
disease, stroke, aortic aneurysm, peripheral artery disease, and
chronic kidney disease. Worldwide, high blood pressure is estimated
to cause 7.5 million deaths, about 12.8% of the total of all
deaths.
[0003] Within the past decades the prevalence of obesity has also
risen in virtually all ethnic, racial and socioeconomic
populations, in both genders and in all age groups. Obesity is
associated with a significantly elevated risk for type 2 diabetes,
coronary heart diseases, hypertension and numerous other major
illnesses and overall mortality from all causes. Therefore, weight
reduction and reduction of blood pressure is usually critical for
the obese patient.
[0004] Control of hypertension is also a major focus area in the
treatment of diabetic subjects since most people with diabetes
develop high blood pressure during their life. Hypertension can
lead to and make worse many complications of diabetes, including
diabetic eye disease and kidney disease.
[0005] Tesofensine, first described in WO 97/30997, is a triple
monoamine reuptake inhibitor in clinical development for the
treatment of obesity. Tesofensine effectively produces weight loss
in obese individuals of about twice of that seen with currently
marketed anti-obesity drugs. In general, tesofensine is well
tolerated in humans, but at therapeutic relevant doses it has been
found that heart rate and, at higher doses, also blood pressure
increased due to a well understood mechanism of action driven
effect (activation of adrenergic receptors) (Astrup et al 2008,
Lancet 372:1906-13). Animal studies have shown that
co-administration of tesofensine and metoprolol is capable of
preventing the tesofensine-induced increase in heart rate and blood
pressure without reducing the weight loss efficacy of tesofensine
(WO 2013/120935 and Hjorth Bentzen et al 2013; Obesity; Vol 21(5),
p. 985-992).
[0006] Metoprolol is a selective .beta.1 (adrenergic) receptor
blocker. Metoprolol has been used to treat various cardiovascular
disorders including angina, arrhythmias, tachycardia, myocardial
infarction, heart failure and hypertension.
[0007] The effect of metoprolol on blood pressure has previously
been investigated (Kostis et al (Circulation 75(1), 204-212, 1987).
Kostis et al has shown that metoprolol treatment decreases supine
systolic and diastolic blood pressure by about 4 mmHg in healthy
male subjects.
[0008] There is impetus for creating new and alternative treatments
for management of hypertension and, in particular, management of
hypertension in obese individuals.
SUMMARY OF INVENTION
[0009] The present inventors have surprisingly found that
co-administration of tesofensine and metoprolol to human subjects
results in a significant decrease in both systolic and diastolic
blood pressure. The observed effect on blood pressure is higher
than the effect achievable from metoprolol alone. The expectation
is that Tesofensine increases blood pressure and that metoprolol
may act to prevent this increase in blood pressure. Therefore it is
unexpected that the combination leads to a decrease in blood
pressure. The blood pressure lowering effect of co-administration
of Tesofensine with Metoprolol has been confirmed in healthy
subjects (example 2) and in subjects with Type 2 diabetes (example
3). The experimental data also confirm that the combination of
Tesofensine with Metoprolol is effective in inducing weight loss
and in reducing blood pressure at the same time.
[0010] Thus, the present invention relates to the use of
tesofensine and metoprolol for reduction of blood pressure, i.e. in
one aspect for treatment of hypertension.
[0011] In a first aspect, the present disclosure relates to a
method for treatment of hypertension in a subject, the method
comprising administering to said subject in need thereof: [0012] i)
a therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0013] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure in said subject.
[0014] In another aspect, the present disclosure relates to a
method for reducing blood pressure in a subject, the method
comprising administering to said subject in need thereof: [0015] i)
a therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0016] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure in said subject.
[0017] The present disclosure further relates to a composition
comprising [0018] i) a therapeutically effective amount of
tesofensine or a pharmaceutically acceptable salt thereof; and
[0019] ii) a therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, for use in the treatment
of hypertension or for reduction of blood pressure.
[0020] In yet another aspect, the present disclosure relates to use
of the composition as described herein in the manufacture of a
medicament for the treatment of hypertension or for reduction of
blood pressure.
[0021] Co-treatment with tesofensine and metoprolol is capable of
reducing both weight and blood pressure in a subject. Thus, in yet
another aspect, the present disclosure relates to a method for
treatment of hypertension and obesity in a subject in need thereof,
the method comprising administering to said subject: [0022] i) a
therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and
[0023] ii) a therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof,
thereby reducing blood pressure and body weight of said
subject.
[0024] The composition comprising tesofensine and metoprolol as
described herein is particularly well suited for use in the
treatment of hypertensive obese and/or diabetic subjects.
DESCRIPTION OF DRAWINGS
[0025] FIG. 1. PK of metoprolol after a single dosing in absence
and presence of tesofensine at steady state. Single dose metoprolol
pharmacokinetics (PK, 50 mg/kg) obtained at day 0 was compared to
the PK obtained after 14 days of tesofensine once daily
administration (2 mg loading dose at days 1-3, 0.5 mg maintenance
dose at days 4-14).
[0026] FIG. 2. Increase in heart rate (HR) caused by 14 days
tesofensine dosing is suppressed by a single metoprolol
administration. Column 1: prelevel HR; column 2: HR after 14 days
of tesofensine; column 3: HR measured on day 14, 7 hours after a
single metoprolol dose in tesofensine treated subjects; column 4:
HR measured on day 15, 24 hours after a single metoprolol dose in
tesofensine treated subjects. *p<0.05 vs tesofensine, ##
p<0.01 vs prelevel. By `t` test Wilcoxon matched-pairs signed
rank test.
[0027] FIG. 3. Systolic and diastolic blood pressure after 14 days
tesofensine dosing followed by a single metoprolol administration.
A single metoprolol administration reduced both systolic and
diastolic blood pressure (BP) in tesofensine treated subjects to
levels below pretreatment levels. Column 1: prelevel BP; column 2:
BP after 14 days of tesofensine; column 3: BP measured on day 14, 7
hours after a single metoprolol dose in tesofensine treated
subjects; column 4: BP measured on day 15, 24 hours after a single
metoprolol dose in tesofensine treated subjects. ** P<0.01 vs
tesofensine (Wilcoxin matched-pairs signed rank test, n=14).
DETAILED DESCRIPTION OF THE INVENTION
[0028] The data in the present application shows that tesofensine
and metoprolol co-administration efficiently reduces blood
pressure, wherefore their combined use is proposed herein for the
treatment of hypertension. The data also confirm that tesofensine
and metoprolol co-administration effectively reduces weight and
blood pressure, wherefore the combined use is proposed herein for
the treatment of hypertension and obesity or an obesity related
disorder as herein defined.
Tesofensine
[0029] The treatment described herein comprises administration of
an active pharmaceutical ingredient (API) selected from tesofensine
or a pharmaceutically acceptable salt thereof.
[0030] Tesofensine
[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicy-
clo[3.2.1]octane] is a centrally acting triple monoamine re-uptake
inhibitor (MRI) with intrinsic inhibitory activity on
noradrenaline, serotonin and dopamine transporter function. When
corrected for placebo and diet effects, long-term tesofensine
treatment produces a weight loss of about 10% in obese patients,
which is approximately twice as much as that achieved by currently
marketed anti-obesity drugs.
[0031] The chemical structure of tesofensine is
##STR00001##
[0032] Preclinical and clinical data suggest that appetite
suppression is an important mechanism by which tesofensine exerts
its robust weight-reducing effect. In addition, tesofensine has
also been demonstrated to increase nocturnal energy expenditure in
human subjects. These findings have recently been corroborated and
extended in preclinical settings, demonstrating that tesofensine
induces a robust and sustained weight loss in a rat model of
diet-induced obesity (DIO) of which the long-lasting reduction in
body weight is caused by appetite suppression with a gradual
increase in energy expenditure. Notably, the hypophagic effect of
tesofensine in DIO rats is critically dependent on stimulated al
adrenoceptor activity, and to a less extend dopamine D1 receptor
function, indicating that enhancement of central noradrenergic and
dopaminergic neurotransmission constitute important mechanisms
underlying the robust appetite-suppressing effect of
tesofensine.
[0033] Overall, chronic tesofensine treatment is associated with
minor adverse events, and with minimal cardiovascular effects,
suggesting that tesofensine may generally be a well-tolerated
long-term treatment for obesity. However, dose-dependent elevations
in heart rate and significant increases in blood pressure have been
reported in obese individuals.
[0034] Examples of pharmaceutically acceptable salts include,
without limitation, the non-toxic inorganic and organic acid
addition salts such as the hydrochloride, the hydrobromide, the
nitrate, the perchlorate, the phosphate, the sulphate, the formate,
the acetate, the aconate, the ascorbate, the benzene-sulphonate,
the benzoate, the cinnamate, the citrate, the embonate, the
enantate, the fumarate, the glutamate, the glycolate, the lactate,
the maleate, the malonate, the mandelate, the methanesulphonate,
the naphthalene-2-sulphonate, the phthalate, the salicylate, the
sorbate, the stearate, the succinate, the tartrate, the
toluene-p-sulphonate, and the like. Such salts may be formed by
procedures well known and described in the art.
[0035] Examples of pharmaceutically acceptable cationic salts of an
API include, without limitation, the sodium, the potassium, the
calcium, the magnesium, the zinc, the aluminium, the lithium, the
choline, the lysinium, and the ammonium salt, and the like, of an
API containing an anionic group. Such cationic salts may be formed
by procedures well known and described in the art.
[0036] In the context of this disclosure the "onium salts" of
N-containing compounds are also contemplated as pharmaceutically
acceptable salts. Preferred "onium salts" include the alkyl-onium
salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium
salts.
[0037] In one embodiment of the present disclosure, tesofensine is
selected from the free base, the citrate salt and the tartrate
salt.
[0038] The tesofensine or pharmaceutically acceptable salt thereof
is usually administered orally.
[0039] Tesofensine is normally administered at a daily dose of
about 0.25-2 mg API (active pharmaceutical ingredient).
[0040] In one embodiment of the present disclosure tesofensine or
pharmaceutical salt thereof is administered at about 0.25 mg or
about 0.5 mg API per day, such as at about 0.2 mg to about 0.3 mg
or about 0.45 to about 0.55 mg API per day.
[0041] In one embodiment of the present disclosure tesofensine or
pharmaceutical salt thereof is administered in a range of from
about 0.1 mg to about 4 mg API per day, such as about 0.1 mg to
about 3 mg API per day, for example about 0.1 to about 2.5 mg API
per day, such as about 0.1 to about 2 mg API per day, such as about
0.1 to about 1.5 mg API per day, for example about 0.1 mg to about
1 mg API per day, such as about 0.1 mg to about 0.8 mg API per day,
for example about 0.1 mg to about 0.7 mg API per day, such as about
0.1 mg to about 0.6 mg API per day, for example about 0.1 mg to
about 0.5 mg API per day, such as about 0.1 mg to about 0.4 mg API
per day, for example about 0.1 mg to about 0.3 mg API per day, such
as about 0.1 mg to about 0.2 or about 0.2 to about 0.3 mg API per
day.
[0042] In one embodiment of the present disclosure tesofensine is
administered in a range of from about 0.5 mg to about 4 mg API per
day, such as about 1 mg to about 4 mg API per day, for example
about 1.5 mg to about 4 mg API per day, such as about 2 mg to about
4 mg API per day.
[0043] In one embodiment, the tesofensine or a pharmaceutically
acceptable salt thereof is administered at 0.1-1.5 mg API per day,
for example 0.1-1 mg API per day, such as 0.2-0.8 mg API per day,
for example 0.25-0.75 mg API per day, such as 0.4-0.6 mg API per
day, for example about 0.2 mg API per day, 0.25 mg API per day, 0.5
mg API per day or 0.75 mg API per day.
[0044] In one embodiment of the present disclosure tesofensine is
administered in a range of from about 0.01 mg to about 0.4 mg API
per day, such as about 0.01 mg to about 0.3 mg API per day, for
example about 0.01 mg to about 0.2 mg API per day, such as about
0.01 mg to about 0.1 mg API per day.
[0045] In one embodiment of the present disclosure tesofensine is
administered in a range of from about 0.05 mg to about 0.4 mg API
per day, such as about 0.05 mg to about 0.3 mg API per day, for
example about 0.05 mg to about 0.2 mg API per day, such as about
0.05 mg to about 0.1 mg API per day.
[0046] In one embodiment of the present disclosure tesofensine is
administered in a range of from about 0.05 mg to about 0.10 mg API
per day, such as about 0.10 mg to about 0.15 mg API per day, for
example about 0.15 mg to about 0.20 mg API per day, such as about
0.20 mg to about 0.25 mg API per day.
[0047] In one embodiment, the tesofensine or a pharmaceutically
acceptable salt thereof is administered at about 0.1-0.3 mg API per
day.
[0048] In one embodiment, the tesofensine or a pharmaceutically
acceptable salt thereof is administered at about 0.2-0.4 mg API per
day.
[0049] In one embodiment, the tesofensine or a pharmaceutically
acceptable salt thereof is administered at about 0.4-0.6 mg API per
day.
[0050] In one embodiment, the tesofensine or a pharmaceutically
acceptable salt thereof is administered at about 0.6-0.8 mg API per
day.
[0051] The daily dosage of tesofensine may be administered in one
or several doses, such as two, per day. In one embodiment, the
daily dosage is administered in one dose.
Metoprolol
[0052] Metoprolol, i.e.
1-(Isopropylamino)-3-[4-(2-methoxyethyl)-phenoxy]-propan-2-ol,
branded under various trade names, is a selective .beta.1
(adrenergic) receptor blocker. Metoprolol has been used to treat
various cardiovascular disorders including angina, arrhythmias,
tachycardia, myocardial infarction, heart failure and hypertension.
The plasma T.sub.1/2 for metoprolol is 3-4 hours.
[0053] Common side effects of metoprolol include trouble sleeping,
feeling tired, feeling faint, and abdominal discomfort. Large doses
may cause serious toxicity. Metoprolol has also been reported to
lead to weight gain (Messerli et al, The American Journal of
Medicine (2007) 120, 610-615).
[0054] Suitable pharmaceutically acceptable salts of metoprolol
include any of the salts mentioned herein and preferably include
the tartrate, succinate, fumarate or benzoate salts and especially
the succinate salt. The S-enantiomer of metoprolol or a salt
thereof, particularly the benzoate salt or the sorbate salt, may
also be used.
[0055] In one embodiment of the present disclosure metoprolol or a
pharmaceutically acceptable salt thereof is administered at 10-200
mg API per day, such as 25-100 mg API per day or 50-150 mg API per
day, for example 80-120 mg API per day, such as 90-110 mg API per
day.
[0056] In one embodiment of the present disclosure metoprolol or a
pharmaceutically acceptable salt thereof is administered at 10-100
mg API per day, such as 10-80 mg API per day, for example 10-50 mg
API per day, such as 10-30 mg API per day.
[0057] The metoprolol or pharmaceutically acceptable salt thereof
is usually administered orally.
[0058] The daily dosage of metoprolol may be administered in one or
several doses per day. In one embodiment, the daily dosage is
administered in two or more doses.
[0059] In one embodiment, the metoprolol is administered as a
pharmaceutical composition having an extended release profile, e.g.
as disclosed in WO 2016/138908 (incorporated by reference).
Co-Administration of Tesofensine and Metoprolol
[0060] According to the present disclosure tesofensine is
co-administered with metoprolol for the treatment or alleviation of
hypertension in a subject in need thereof. Preferably, the
treatment disclosed herein results in a reduction of blood pressure
exceeding that of metoprolol treatment alone.
[0061] Thus, in one embodiment, the present disclosure relates to a
method for treatment of hypertension in a subject, the method
comprising administering to said subject in need thereof: [0062] i)
a therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0063] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure in said subject.
[0064] Hypertension usually does not cause symptoms initially, but
sustained hypertension over time is a major risk factor for
hypertensive heart disease, coronary artery disease, stroke, aortic
aneurysm, peripheral artery disease, and chronic kidney
disease.
[0065] Blood pressure is expressed by two measurements, the
systolic and diastolic pressures, which are the maximum and minimum
pressures, respectively, in the arterial system. The systolic
pressure occurs when the left ventricle is most contracted; the
diastolic pressure occurs when the left ventricle is most relaxed
prior to the next contraction. The blood pressure values given
herein represent values at rest, e.g. supine blood pressure, unless
otherwise indicated.
[0066] In people aged 18 years or older hypertension is defined as
a systolic and/or a diastolic blood pressure consistently higher
than an accepted normal value--see table herein below.
TABLE-US-00001 Category Systolic, mm Hg Diastolic, mm Hg Normal
90-119 60-79 High Normal (pre-hypertension) 120-139 80-89 Stage 1
hypertension 140-159 90-99 Stage 2 hypertension 160-179 100-109
Stage 3 hypertension .gtoreq.180 .gtoreq.110 (hypertensive
emergency) Isolated systolic hypertension .gtoreq.140 <90
[0067] In some instances, lower thresholds for classification of
hypertension may be used (135 mmHg systolic or 85 mmHg diastolic),
e.g. if measurements are derived from 24-hour ambulatory or home
monitoring.
[0068] Treatment of hypertension is to be understood herein as a
reduction in blood pressure considered clinically relevant by the
skilled person. Clinical trials demonstrate that lowering blood
pressure can substantially reduce cardiovascular risk, and current
clinical practice guidelines identify lowering blood pressure as a
priority in the treatment of people with hypertension.
[0069] Preferably, the treatment described herein results in a
decrease in the systolic blood pressure and/or a decrease in the
diastolic blood pressure.
[0070] In one embodiment, the subject treated according to the
methods of the present disclosure is a pre-hypertensive subject
having a systolic blood pressure in the range of 120-139 mmHg and a
diastolic blood pressure in the range of 80-89 mmHg.
[0071] In one embodiment, the subject has a systolic blood pressure
above 135 mmHg and/or a diastolic blood pressure above 85 mmHg.
[0072] In one embodiment, the subject has a systolic blood pressure
above 140 mmHg and/or a diastolic blood pressure above 90 mmHg.
[0073] In one embodiment, the subject suffers from stage 1
hypertension, i.e. said subject has a systolic blood pressure in
the range of 140-159 mmHg and a diastolic blood pressure in the
range of 90-99 mmHg.
[0074] In one embodiment, the subject suffers from stage 2
hypertension, i.e. said subject has a systolic blood pressure in
the range of 160-179 mmHg and a diastolic blood pressure in the
range of 100-109 mmHg.
[0075] In one embodiment, the subject suffers from stage 3
hypertension, i.e. said subject has a systolic blood pressure at or
above 180 mmHg and a diastolic blood pressure at or above 110
mmHg.
[0076] In one embodiment, the subject suffers from isolated
systolic hypertension, i.e. said subject has a systolic blood
pressure at or above 140 mmHg and a diastolic blood pressure below
90 mmHg.
[0077] In children and adolescents (<18 years), hypertension is
defined as elevated blood pressure over several visits (The Fourth
Report on the Diagnosis, Evaluation, and Treatment of High Blood
Pressure in Children and Adolescents; Pediatrics, August 2004,
VOLUME 114/ISSUE Supplement 2). The definition of hypertension in
children and adolescents is based on the normative distribution of
blood pressure (BP) in healthy children. Normal BP is defined as
systolic blood pressure (SBP) and diastolic blood pressure (DBP)
that are <90th percentile for gender, age, and height.
Hypertension is defined as average SBP or DBP that is 95th
percentile for gender, age, and height on at least 3 separate
occasions. Average SBP or DBP levels that are 90th percentile but
<95th percentile had been designated as "high normal" and were
considered to be an indication of heightened risk for developing
hypertension. It is now recommended that, as with adults, children
and adolescents with BP levels 120/80 mm Hg but <95th percentile
should be considered prehypertensive.
[0078] In one embodiment the subject is below 18 years of age.
Children with hypertension may suffer from one or more of diabetes,
pre-diabetes, obesity, overeating or Prader Willi syndrome.
[0079] In one embodiment, the treatment results in a decrease in
the systolic blood pressure by at least 5 mm Hg, for example at
least 6 mm Hg, such as at least 7 mm Hg, for example at least 8 mm
Hg, such as at least 9 mm Hg, for example at least 10 mm Hg, such
as at least 12 mm Hg, for example at least 15 mm Hg, such as at
least 17 mm Hg, for example at least 20 mm Hg, such as at least 22
mm Hg, for example at least 25 mm Hg, such as at least 27 mm Hg,
for example at least 30 mm Hg.
[0080] In one embodiment, the treatment results in a decrease in
the systolic blood pressure by at least 10 mm Hg.
[0081] In one embodiment the treatment results in a decrease in the
systolic blood pressure by at least 5%, such as at least 7%, for
example at least 10%, such as at least 12%, for example at least
15%, such as at least 17%, for example at least 20%, such as at
least 22%, for example at least 25%.
[0082] In one embodiment, the treatment results in a decrease in
the diastolic blood pressure by at least 5 mm Hg, for example at
least 6 mm Hg, such as at least 7 mm Hg, for example at least 8 mm
Hg, such as at least 9 mm Hg, for example at least 10 mm Hg, such
as at least 12 mm Hg, for example at least 15 mm Hg, such as at
least 17 mm Hg, for example at least 20 mm Hg, such as at least 22
mm Hg, for example at least 25 mm Hg, such as at least 27 mm Hg,
for example at least 30 mm Hg.
[0083] In one embodiment, the treatment results in a decrease in
the diastolic blood pressure by at least 10 mm Hg.
[0084] In one embodiment, the treatment results in a decrease in
the diastolic blood pressure by at least 5%, such as at least 7%,
for example at least 10%, such as at least 12%, for example at
least 15%, such as at least 17%, for example at least 20%, such as
at least 22%, for example at least 25%.
[0085] Control of hypertension is a particular focus area in obese
subjects, since subjects suffering from obesity often also suffer
from hypertension. The present treatment allows for concurrent
treatment of hypertension and obesity. Obesity is defined herein as
a medical condition in which excess body fat has accumulated to the
extent that it may have an adverse effect on health, leading to
reduced life expectancy and/or increased health problems in
general. Thus, in one embodiment the subject is obese.
[0086] Body mass index (BMI) is a measure which compares weight and
height. People are generally considered overweight or pre-obese if
the BMI is between 25 and 30 and obese if the BMI is over 30.
Morbidly obese subjects have a BMI over 35.
[0087] In one embodiment the subject has a BMI above 25 kg/m.sup.2,
such as above 30 kg/m.sup.2, for example above 35 kg/m.sup.2, such
as above 40 kg/m.sup.2.
[0088] In one embodiment the subject has a BMI above 30
kg/m.sup.2.
[0089] In one embodiment the subject has a BMI above 35
kg/m.sup.2.
[0090] Most people with diabetes develop high blood pressure during
their life. Hypertension substantially increases the risk of
diabetic complications. Diabetic complications include but are not
limited to macrovascular and microvascular complications, including
stroke, coronary artery disease, and peripheral vascular disease,
retinopathy, nephropathy, and possibly neuropathy. Hypertension may
also lead to worsening of diabetic complications. Thus, control or
alleviation of hypertension is often an important aspect in the
treatment of diabetic subjects.
[0091] In one embodiment, the tesofensine-metoprolol treatment
described herein leads to an alleviation or improvement of diabetic
complications.
[0092] In one embodiment, the subject is suffering from diabetes,
such as type 1 diabetes, type 2 diabetes, pre-diabetes and
gestational diabetes.
[0093] In one embodiment, the subject is suffering from type 1
diabetes.
[0094] In one embodiment, the subject is suffering from type 2
diabetes.
[0095] In one embodiment, the subject is suffering from
pre-diabetes.
[0096] In one embodiment, the subject is suffering from gestational
diabetes.
[0097] Type 1 diabetes (diabetes mellitus type 1) is a form of
diabetes that results from the autoimmune destruction of the
insulin-producing beta cells in the pancreas. In type 1 diabetes,
hypertension may reflect the onset of diabetic nephropathy.
[0098] Type 2 diabetes is a metabolic disorder that is
characterized by hyperglycemia in the context of insulin resistance
and a relative lack of insulin. Type 2 diabetes makes up about 90%
of cases of diabetes, with the other 10% due primarily to diabetes
mellitus type 1 and gestational diabetes. Obesity is thought to be
the primary cause of type 2 diabetes in people who are genetically
predisposed to the disease. In type 2 diabetes, hypertension is
often present as part of the metabolic syndrome of insulin
resistance also including central obesity and dyslipidemia.
[0099] Pre-diabetes is used interchangeably herein with
intermediate hyperglycaemia. Intermediate hyperglycaemia is a
biochemical state in which a person has glucose levels above the
normal range, but does not yet meet the criteria for a diagnosis of
diabetes. The primary aim of management of intermediate
hyperglycaemia is to prevent progression to diabetes.
[0100] A pre-diabetic subject may have one or more of impaired
fasting glycaemia (IFG) and/or impaired glucose tolerance (IGT)
and/or elevated glycated haemoglobin (HbA.sub.1c) levels.
[0101] Weight loss can prevent progression of pre-diabetes into
diabetes and can also markedly improve clinical symptoms of type 2
diabetes. Thus, weight loss is an attractive treatment strategy for
pre-diabetic subjects and subjects suffering from type 2
diabetes.
[0102] In one embodiment the subject is an obese, pre-diabetic
human. In one embodiment the subject is an obese subject suffering
from type 2 diabetes.
[0103] Gestational diabetes is a condition in which women without
previously diagnosed diabetes exhibit high blood glucose levels
during pregnancy (especially during their third trimester).
Gestational diabetes is caused when insulin receptors do not
function properly.
[0104] The WHO diabetes diagnostic criteria are shown in the table
below.
TABLE-US-00002 2 hour glucose* Fasting glucose HbA.sub.1c mmol/l
mmol/l mmol/mol Condition (mg/dl) (mg/dl) (DCCT %) Normal <7.8
(<140) <6.1 (<110) <42 (<6.0) Impaired <7.8
(<140) .gtoreq.6.1 (.gtoreq.110) & 42-46 (6.0-6.4) fasting
<7.0 (<126) glycaemia Impaired .gtoreq.7.8 (.gtoreq.140)
<7.0 (<126) 42-46 (6.0-6.4) glucose tolerance Diabetes
.gtoreq.11.1 (.gtoreq.200) .gtoreq.7.0 (.gtoreq.126) .gtoreq.48
(.gtoreq.6.5) mellitus *Venous plasma glucose 2 hours after
ingestion of 75 g oral glucose load
[0105] The subject benefitting from co-treatment of tesofensine and
metoprolol according to the methods of the present invention may
also be a subject suffering from an obesity-associated disorder or
condition, such as one selected from the group consisting of
metabolic syndrome, dyslipidemia, atherosclerosis, drug-induced
obesity, overeating disorders, bulimia nervosa, binge eating
disorder, compulsive over-eating, impaired appetite regulation,
Prader-Willi Syndrome, nonalcoholic fatty liver disease (NAFLD) and
nonalcoholic steatohepatitis (NASH).
[0106] In one embodiment the subject is suffering from metabolic
syndrome.
[0107] In one embodiment, the subject is suffering from Prader
Willi syndrome. Prader-Willi syndrome (PWS) is a genetic disorder
due to loss of function of specific genes on chromosome 15. In
newborns symptoms include weak muscles, poor feeding, and slow
development. In childhood the person becomes constantly hungry
which often leads to obesity and type 2 diabetes.
[0108] In one embodiment the subject is suffering from a fatty
liver disease selected from nonalcoholic fatty liver disease
(NAFLD) and nonalcoholic steatohepatitis (NASH).
[0109] Nonalcoholic fatty liver disease (NAFLD) is a cause of a
fatty liver, occurring when fat is deposited in the liver
(steatosis) due to other causes than excessive alcohol use. NAFLD
is the most common liver disorder in Western industrialized
nations. NAFLD is associated with insulin resistance and metabolic
syndrome (obesity, combined hyperlipidemia, diabetes mellitus (type
II) and high blood pressure). Non-alcoholic steatohepatitis (NASH)
is the most extreme form of NAFLD, and is a major cause of
cirrhosis of the liver. NASH is a state in which the steatosis is
combined with inflammation and fibrosis (steatohepatitis).
[0110] In one embodiment, the obesity-associated disorder or
condition is nonalcoholic fatty liver disease (NAFLD).
[0111] In one embodiment, the obesity-associated disorder or
condition is nonalcoholic steatohepatitis (NASH).
[0112] In one embodiment, the present disclosure relates to a
method for co-treatment of hypertension and obesity in a subject in
need thereof, the method comprising administering to said subject:
[0113] i) a therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0114] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure and body weight of said subject.
[0115] Co-administration of tesofensine and metoprolol is capable
of preventing cardiovascular side-effects of tesofensine, i.e.
prevent increases in heart rate and blood pressure induced by
tesofensine. Thus, in one embodiment, the present disclosure
further relates to prevention or alleviation of cardiovascular
side-effects of tesofensine.
[0116] In one embodiment, the present disclosure relates to a
method for reduction of weight and blood pressure in a subject in
need thereof, the method comprising administering to said subject:
[0117] i) a therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0118] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure and weight of said subject.
[0119] In one embodiment, the present disclosure relates to a
method for co-treatment of hypertension and diabetes (in particular
type 2 diabetes) in a subject in need thereof, the method
comprising administering to said subject: [0120] i) a
therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0121] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure and treating diabetes of said subject.
[0122] In one embodiment, the present disclosure relates to a
method for co-treatment of hypertension and an obesity related
disorder as herein defined in a subject in need thereof, the method
comprising administering to said subject: [0123] i) a
therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0124] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure and treating the obesity related disorder of said
subject.
[0125] In one embodiment, the present disclosure relates to a
method for co-treatment of hypertension and a fatty liver disease,
such as NAFLD or NASH, in a subject in need thereof, the method
comprising administering to said subject: [0126] i) a
therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0127] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof, thereby reducing blood
pressure and treating the fatty liver disease of said subject.
[0128] In one embodiment the present disclosure relates to a method
for treatment of hypertension, obesity and diabetes in a subject in
need thereof, the method comprising administering to said subject:
[0129] i) a therapeutically effective amount of tesofensine or a
pharmaceutically acceptable salt thereof; and [0130] ii) a
therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof.
[0131] In one embodiment the present disclosure relates to a method
for treating, alleviating or preventing diabetic complications in a
subject in need thereof, the method comprising administering to
said subject: [0132] i) a therapeutically effective amount of
tesofensine or a pharmaceutically acceptable salt thereof; and
[0133] ii) a therapeutically effective amount of metoprolol or a
pharmaceutically acceptable salt thereof.
[0134] In one embodiment, the present disclosure relates to a
composition comprising tesofensine or a pharmaceutically acceptable
salt thereof and metoprolol or a pharmaceutically acceptable salt
thereof, for use in the treatment of hypertension.
[0135] In one embodiment, the present disclosure relates to a
composition comprising tesofensine or a pharmaceutically acceptable
salt thereof and metoprolol or a pharmaceutically acceptable salt
thereof, for use in the treatment of hypertension and obesity.
[0136] In one embodiment, the present disclosure relates to a
composition comprising tesofensine or a pharmaceutically acceptable
salt thereof and metoprolol or a pharmaceutically acceptable salt
thereof, for use in the treatment of hypertension and diabetes.
[0137] In one embodiment, the present disclosure relates to a
composition comprising tesofensine or a pharmaceutically acceptable
salt thereof and metoprolol or a pharmaceutically acceptable salt
thereof, for use in the treatment of hypertension and a fatty liver
disorder.
[0138] In one embodiment, the present disclosure relates to a
composition comprising tesofensine or a pharmaceutically acceptable
salt thereof and metoprolol or a pharmaceutically acceptable salt
thereof, for use in the treatment of hypertension and an obesity
related disorder as herein defined.
[0139] In one embodiment, the present disclosure relates to a
composition comprising tesofensine or a pharmaceutically acceptable
salt thereof and metoprolol or a pharmaceutically acceptable salt
thereof, for use in the treatment of hypertension, obesity and
diabetes.
[0140] In one embodiment, the present disclosure relates to a
composition comprising tesofensine or a pharmaceutically acceptable
salt thereof and metoprolol or a pharmaceutically acceptable salt
thereof, for use in treating, alleviating or preventing diabetic
complications.
[0141] In one embodiment, the present disclosure relates to the use
of a composition comprising tesofensine or a pharmaceutically
acceptable salt thereof and metoprolol or a pharmaceutically
acceptable salt thereof, for the manufacture of a medicament for
the treatment of hypertension, optionally further for the treatment
of obesity and/or diabetes.
[0142] The tesofensine and metoprolol according to the present
disclosure may be administered simultaneously, sequentially or
separately.
[0143] In one embodiment, the tesofensine and the metoprolol are
co-administered as a single composition. In such compositions, at
least part of the metoprolol may advantageously be formulated to
exhibit an extended release profile. In one embodiment, the
composition comprising tesofensine and metoprolol is as described
in WO 2016/138908 (claiming priority from PA 2015 70117 and PA 2015
70644), which are incorporated by reference in their entirety.
[0144] An example of a single composition comprising both
tesofensine and metoprolol is a pharmaceutical composition
comprising
a. a first composition comprising an extended release (ER)
composition of metoprolol or a pharmaceutically acceptable salt
thereof, b. a second composition comprising tesofensine or a
pharmaceutically acceptable salt thereof, and c. a third
composition comprising an immediate release (IR) composition with
metoprolol or a pharmaceutically acceptable salt thereof.
[0145] In one embodiment Tesofensine and Metoprolol are present in
one dosage form with three phases in the following absolute amounts
per dosage form.
TABLE-US-00003 Metoprolol extended Metoprolol immediate Tesofensine
immediate release release release 20-200 mg 5-50 mg 0.1-1.5 mg
75-125 mg 10-25 mg 0.25-0.75 mg 75-80 mg 10-15 mg 0.25-0.75 mg 100
mg 25 mg 0.5 mg 100 mg 10 mg 0.5 mg 80 mg 20 mg 0.5 mg 20 mg 5 mg
0.2 mg
[0146] In one embodiment, the dosage form comprises a tri-layer
dosage unit having an extended release (ER) phase layer with
metoprolol, and one immediate release phase layer with metoprolol
and another immediate release layer with tesofensine. The ER phase
contains a therapeutically effective amount of metoprolol, suitably
in granulate form.
[0147] In other embodiments, the dosage form is a bi-layer tablet
having an ER phase layer with metoprolol and one immediate release
layer with both metoprolol and tesofensine.
[0148] The composition comprising tesofensine and metoprolol may
further comprise one or more adjuvants, excipients, carriers and/or
diluents.
[0149] In some embodiments, the composition comprising tesofensine
and metoprolol may comprise one or more further therapeutic and/or
prophylactic agents known in the art to treat hypertension and/or
obesity and/or diabetes.
[0150] The tesofensine and metoprolol may be administered by any
convenient route, which suits the desired therapy. Preferred routes
of administration include oral administration, in particular in
tablet, in capsule, in drage, in powder, or in liquid form, and
parenteral administration, in particular cutaneous, subcutaneous,
intramuscular, or intravenous injection. Preferably, the
tesofensine and metoprolol are administered orally.
[0151] Compositions comprising tesofensine and metoprolol as
described herein may be manufactured by the skilled person by use
of standard methods and conventional techniques appropriate to the
desired formulation. When desired, compositions adapted to give
sustained release of the active ingredient may be employed.
[0152] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0153] The subject treated is preferably a human, such as an adult
human aged 18 or older. In other embodiments the subject is a child
or an adolescent below 18 years of age.
[0154] The data in the present application shows that
co-administration of tesofensine and metoprolol unexpectedly result
in a significant decrease in both systolic and diastolic blood
pressure. The effect on blood pressure in response to
co-administration of tesofensine and metoprolol is greater than has
been shown by metoprolol alone (Kostis et al (Circulation 75(1),
204-212, 1987).
[0155] Thus, in one embodiment, the present disclosure relates to a
method for improving the therapeutic effect of metoprolol,
particularly for improving the effect of metoprolol on blood
pressure, the method comprising co-administration of metoprolol and
tesofensine as described herein to a subject in need thereof.
EXAMPLES
Example 1. Effect of Tesofensine on Metoprolol Pharmacokinetics
[0156] The ability of tesofensine to inhibit CYP2D6 in the clinical
setting was investigated in a Phase 1 drug-drug interaction (DDI)
study with metoprolol, which is a known substrate for CYP2D6.
Subjects
[0157] Healthy human male volunteers, 18-50 years of age. A total
of 14 subjects were included in the study.
Methodology
[0158] Two consecutive study periods separated by a washout period
of at least three days. The sequence of events was the same for all
subjects. In period 1, a single dose of metoprolol was
administered. In period 2, the same dose of metoprolol was
administered at a steady state concentration of tesofensine.
Metoprolol: 50 mg single dose Tesofensine: 2 mg loading dose at
days 1-3, 0.5 mg maintenance dose at days 4-14
Results
[0159] The single dose metoprolol pharmacokinetics (PK) obtained at
day 0 was compared to the PK obtained after 14 days of tesofensine
once daily administration.
[0160] The results are depicted in FIG. 1. The results show that
tesofensine caused a small (15%), but statistically significant
increase in metoprolol AUC with no effect on either Tmax or Cmax.
The results indicate that tesofensine is capable of increasing the
bioavailability of metoprolol through its inhibitory action on
CYP2D6.
Example 2. Effect of Tesofensine and Metoprolol on Heart Rate and
Blood Pressure in Humans
[0161] In a retrospective analysis of the data obtained in the
above-mentioned Phase 1 DDI study the effect of a single dose of
metoprolol in subjects treated with tesofensine was investigated.
Particularly, the effect of tesofensine-metoprolol on heart rate
and blood pressure at rest, was investigated.
[0162] Metoprolol was found to normalize the tesofensine-induced
increase in heart rate after 7 hours (FIG. 2, 3.sup.rd column) as
previously shown pre-clinically. In accordance with the
pharmacokinetics of metoprolol (plasma T.sub.1/2 3-4 hours)--the
effect on the heart rate disappeared after .about.24 hours (FIG. 2,
4.sup.th column). The data indicates that co-administration of
tesofensine and metoprolol is capable of inhibiting the
tesofensine-induced increase in heart rate in human subjects to
levels approximating pre-treatment levels.
[0163] In the present study, 14 days of tesofensine treatment was
found to increase systolic BP slightly, while diastolic BP was
essentially not altered by tesofensine treatment (FIG. 3, column
2). The slight increase in systolic BP in response to tesofensine
treatment was not significant. However, statistically significant
decreases in the systolic and diastolic blood pressures were
observed after metoprolol administration at day 14 (FIG. 3, column
3) as compared to pre-treatment levels and also compared to
subjects treated with tesofensine only. Systolic BP in response to
tesofensine-metoprolol co-administration was found to be decreased
by about 11 mm Hg as compared to pre-treatment levels and by about
14 mm Hg as compared to subjects treated with tesofensine only.
Diastolic BP in response to tesofensine-metoprolol
co-administration was found to be decreased by about 12 mm Hg as
compared to pre-treatment levels and by about 13 mm Hg as compared
to subjects treated with tesofensine only. This corresponds to a
decrease in systolic BP by more than 8% and a decrease in diastolic
BP by more than 15% as compared to pre-treatment levels.
[0164] The data presented herein indicates that co-administration
of tesofensine and metoprolol significantly reduce both systolic
and diastolic BP to a larger degree than metoprolol treatment alone
(Kostis et al (Circulation 75(1), 204-212, 1987). Thus, the data
herein indicates that tesofensine and metoprolol co-administration
is an attractive treatment strategy for hypertensive subjects. In
particular for treatment of obese hypertensive subjects as such
subjects would benefit greatly from both the weight-reducing effect
of tesofensine and the BP-lowering effect of tesofensine and
metoprolol.
[0165] As shown herein, tesofensine may increase bioavailability of
metoprolol slightly through its inhibitory effect on CYP2D6
(Example 1). However, it is unlikely that the significant decrease
in blood pressure described herein in human subjects in response to
tesofensine-metoprolol co-administration can be explained solely by
this action. Additionally, the blood pressure lowering effect of
tesofensine-metoprolol co-administration was highly surprising in
view of animal studies showing that co-administration of
tesofensine and metoprolol merely prevented tesofensine-induced
increases in heart rate and blood pressure (WO 2013/120935 and
Hjorth Bentzen et al 2013; Obesity; Vol 21(5), p. 985-992).
Example 3 Phase 2a Trial Entitled "A Double-Blind, Randomized,
Placebo-Controlled, Multiple-Dose, Two-Center Safety, and Efficacy
Study of Co-Administration of Tesofensin/Metoprolol (Tesomet) in
Subjects with Type 2 Diabetes Mellitus (NCT02737891)
[0166] The trial comprised a total of 60 patients with a mean BMI
of 32.59 randomized into two groups of each 30 patients: Arm 1 were
administered tesofensine 0.5 mg (tablets)+metoprolol 100 mg
(MetoHEXAL.RTM. 100 mg retard tablets) once a day (Tesomet); Arm 2
were administered Placebo matching tablets once a day. Patients
were treated for 90 days. The patients at enrolment had an average
BMI of 32.59.
Inclusion Criteria:
[0167] 1. Males and females 2. Confirmed diagnosis of T2DM 3. 18-70
years of age
4. HbA1c.gtoreq.7.0%
Exclusion Criteria:
[0168] 1. Hypersensitivity to tesofensine/metoprolol 2. Heart
failure class II or greater according to the New York Heart
Association (NYHA) or decompensated heart failure 3. History of
myocardial infarction or stroke within 12 months prior to enrolment
4. History of coronary revascularisation or angioplasty in the last
12 months prior to enrolment 5. Patients reporting angina in the
last 6 months prior to enrolment 6. Treatment with insulin and/or
other injectable anti-diabetic medications, or TZDs 7. Any
clinically significant cardiac arrhythmia
Results
[0169] 58 patients completed the study. The study demonstrated a
statistically significant reduction in bodyweight during the course
of the study (day 0 to day 90) of 3.50 kg (3.54%) in the treatment
group compared to a reduction of 0.29 kg (0.31%) in the placebo
group (p<0.0001). The reduction in body weight correlated with a
decrease in waist circumference of 2.29 cm in the Tesomet treatment
group compared to a reduction of 0.03 cm for patients receiving
placebo (p<0.007).
[0170] Both systolic and diastolic blood pressures were numerically
reduced in the treatment group from baseline at day 0 to day 90.
Systolic blood pressure was numerically reduced by an average of
3.10 mmHg for patients treated with Tesomet compared to an average
decrease of 0.66 mmHg for patients dosed with placebo. Diastolic
blood pressure was numerically reduced by an average of 2.21 mmHg
for patients treated with Tesomet compared to an average decrease
of 0.19 mmHg for patients dosed with placebo.
* * * * *