Note: Descriptions are shown in the official language in which they were submitted.
CA 02685638 2009-11-13
Sanofi Aventis Deutschland GmbH DE2009/200 Dr. Fl
Method of treatment of diabetes type 2 comprising add-on therapy to insulin
glargine
and metformin
Description
Subject of the present invention is a method for treatment of diabetes type 2
with
AVE0010 (lixisenatide) as add-on therapy to administration of insulin glargine
and
metformin.
Metformin is a biguanide hypoglycemic agent used in the treatment of Type 2
diabetes mellitus not responding to dietary modification. Metformin improves
glycemic control by improving insulin sensitivity. Metformin is usually
administered
orally.
Insulin is a polypeptide having 51 amino acid residues. Insulin consists of
the A
chain having 21 amino acid residues, and the B chain having 30 amino acid
residues. The chains are coupled by 2 disulfide bridges. Insulin formulations
have
been used for a long time for therapy of diabetes mellitus type 1 and 2.
Recently,
insulin derivatives and insulin analogues have been used.
However, control diabetes mellitus type 2 by metformin and insulin may be
insufficient. Thus, in these patients, additional measures for controlling
diabetes
mellitus type 2 may be required.
A first aspect of the present invention is a method for the treatment of
diabetes
mellitus type 2 comprising administering
(a) desPro36Exendin-4(1-39)-Lys6-NH2 (AVE0010, lixisenatide) or/and a
pharmaceutically acceptable salt thereof,
(b) insulin glargine or/and a pharmaceutically acceptable salt thereof, and
(c) metformin or/and a pharmaceutically acceptable salt thereof,
to a subject in need thereof.
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The compounds of (a), (b) and (c) may be administered to a subject in need
thereof,
in an amount sufficient to induce a therapeutic effect.
The compound desPro36Exendin-4(1-39)-Lys6-NH2 (AVE0010, lixisenatide) is a
derivative of Exendin-4. AVE0010 is disclosed as SEQ ID NO:93 in WO 01/04156:
= SEQ ID NO: 1 AVE0010 (44 AS)
H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-
S-K-K-K-K-K-K-NH2
= SEQ ID NO: 2 Exendin-4 (39 AS)
H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-
P-S-NH2
Exendins are a group of peptides which can lower blood glucose concentration.
The
Exendin analogue AVE0010 is characterised by C-terminal truncation of the
native
Exendin-4 sequence. AVE0010 comprises six C-terminal lysine residues not
present
in Exendin-4.
In the context of the present invention, AVE0010 includes pharmaceutically
acceptable salts thereof. The person skilled in the art knows pharmaceutically
acceptable salts of AVE0010. A preferred pharmaceutically acceptable salt of
AVE0010 employed in the present invention is acetate.
AVE0010 (desPro36Exendin-4(1-39)-Lys6-NH2) or/and a pharmaceutically
acceptable salt thereof may be administered parenterally, e.g. by subcutaneous
injection. Suitable injection devices, for instance the so-called "pens"
comprising a
cartridge comprising the active ingredient, and an injection needle, are
known.
AVE0010 or/and a pharmaceutically acceptable salt thereof may be administered
in
a suitable amount, for instance in an amount in the range of 10 to 15 pg per
dose or
15 to 20 pg per dose once a day (progressive titration from 10 to 15 and to 20
pg
/day. 20 pg is the effective maintenance dose).
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In the present invention, AVE0010 or/and a pharmaceutically acceptable salt
thereof
may be administered in a daily dose in the range of 10 to 15 pg or in the
range of 15
to 20 pg (progressive titration from 10 to 15 and to 20 pg /day. 20 pg is the
effective
maintenance dose). AVE0010 or/and a pharmaceutically acceptable salt thereof
may
be administered by one injection per day.
Insulin glargine (Lantus) is Gly(A21)-Arg(B31)-Arg(B32)-human insulin. In the
context of the present invention, insulin glargine includes pharmaceutically
acceptable salts thereof.
Insulin glargine or/and a pharmaceutically acceptable salt thereof may be
administered by injection (by subcutaneous injection). Suitable injection
devices, for
instance the so-called "pens" comprising a cartridge comprising the active
ingredient,
and an injection needle, are known. Insulin glargine or/and a pharmaceutically
acceptable salt thereof may be administered in a suitable amount, for instance
in an
amount of at least 10 units per day (the initial dose is 10 units; 80 units is
the
maximal dose possible with the pen with 1 injection)
In the present invention, insulin glargine or/and a pharmaceutically
acceptable salt
thereof may be administered in a daily dose of at least 10 units. Insulin
glargine
or/and a pharmaceutically acceptable salt thereof may be administered by one
injection per day.
In the present invention, AVE0010 or/and a pharmaceutically acceptable salt
thereof
may be provided in a liquid composition The skilled person knows liquid
compositions of AVE0010 suitable for subcutaneous administration.
In the present invention, insulin glargine or/and a pharmaceutically
acceptable salt
thereof may be provided in a liquid composition The skilled person knows
liquid
compositions of insulin glargine suitable for subcutaneous administration.
A liquid composition employed herein may have an acidic or a physiologic pH.
An
acidic pH preferably is in the range of pH 1 - 6.8, pH 3.5 - 6.8, or pH 3.5 -
5. A
physiologic pH preferably is in the range of pH 2.5 -8.5, pH 4.0 to 8.5, or pH
6.0 to
8.5. The pH may be adjusted by a pharmaceutically acceptable diluted acid
(typically
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HCI) or pharmaceutically acceptable diluted base (typically NaOH).
The preferred pH is in the range of pH 3,5 to 5,0.
The liquid composition may contain a buffer, such as a phosphate, a citrate,
an
acetate. Preferably, it can contain an acetate buffer, in quantities up to 5
pg/mL, up
to 4 pg/mL or up to 2 pg/mL.
The liquid composition employed herein may comprise a suitable preservative. A
suitable preservative may be selected from phenol, m-cresol, benzyl alcohol
and p-
hydroxybenzoic acid ester. A preferred preservative is m-cresol. However, the
preferred liquid composition does not contain a preservative.
The liquid composition employed herein may comprise a tonicity agent. A
suitable
tonicity agent may be selected from glycerol, lactose, sorbitol, mannitol,
glucose,
NaCl, calcium or magnesium containing compounds such as CaCl2. The
concentration of glycerol, lactose, sorbitol, mannitol and glucose may be in
the range
of 100 - 250 mM. The concentration of NaCl may be up to 150 mM. A preferred
tonicity agent is glycerol.
In addition, the liquid composition may contain L-methionin from 0,5 pg/mL to
20 pg/mL, preferably from 1 pg/mL to 5 pg/mL. Preferably it contains L-
methionin.
Metformin is the international nonproprietary name of 1,1-dimethylbiguanide
(CAS
Number 657-24-9). In the present invention, the term "metformin" includes any
pharmaceutically acceptable salt thereof.
In the present invention, metformin may be administered orally. The skilled
person
knows formulations of metformin suitable for treatment of diabetes type 2 by
oral
administration. Metformin may be administered in a dose of at least 1.5 g/day.
For
oral administration, metformin may be formulated in a solid dosage form, such
as a
tablet or pill.
In the present invention, desPro36Exendin-4(1-39)-Lys6-NH2 or/and a
pharmaceutically acceptable salt is administered in an add-on therapy to
CA 02685638 2009-11-13
administration of metformin and insulin glargine.
In the present invention, the terms "add-on", "add-on treatment" and "add-on
therapy" relate to treatment of diabetes mellitus type 2 with metformin,
insulin
5 glargine and AVE0010. Metformin, insulin glargine and AVE0010 may be
administered within a time interval of 24 h. Metformin, insulin glargine and
AVE0010
each may be administered in a once-a-day-dosage. Metformin may be administered
by a different administration route than insulin glargine and AVE0010.
Metformin
may be administered orally, whereas AVE0010 and insulin glargine may be
administered subcutaneously.
The subject to be treated by the method of the present invention may have a
fasting
plasma glucose concentration of at least 7 mmol/L or/and 2 hours postprandial
plasma glucose of at least 11.1 mmol/L. The subject may have a HbAlc value in
the
range of 7% to 10%.
The subject to be treated by the method of the present invention may be an
adult
subject. The subject may have an age in the range of 18 to 50 years.
The method of the present invention preferably is a method of treatment of a
subject
suffering from diabetes type 2, wherein diabetes type 2 is not adequately
controlled
by treatment with metformin and insulin alone, for instance with a dose of at
least 1.5
g/day metformin and a dose of insulin of at least 10 units, preferably of 15
to 80
May for 3 months.
Another aspect of the present invention is a pharmaceutical combination
comprising
(a) desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable
salt thereof,
(b) insulin glargine or/and a pharmaceutically acceptable salt thereof, and
(c) metformin or/and a pharmaceutically acceptable salt thereof.
Preferably, the combination of the present invention is for treatment of
diabetes
mellitus type 2.
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The combination of the present invention may be administered as described
herein
in the context of the method of the present invention. The compounds (a), (b)
and (c)
of the combination of the present invention may be formulated as described
herein in
the context of the method of the present invention.
Yet another aspect of the present invention is the use of a combination
comprising
(a) desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable
salt thereof,
(b) insulin glargine or/and a pharmaceutically acceptable salt thereof, and
(c) metformin or/and a pharmaceutically acceptable salt thereof,
for the production of a medicament for the treatment of diabetes mellitus type
2.
The medicament comprises desPro36Exendin-4(1-39)-Lys6-NH2, insulin glargine
and metformin in separate formulations, as described herein.
The invention is further illustrated by the following example.
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Example
24-week treatment of diabetes type 2 with lixisenatide (AVE0010) as add-on
therapy
to insulin glargine and metformin
Subject of the example is a randomized, placebo-controlled, 2-arm parallel-
group,
multicenter study with a 24-week double-blind treatment period assessing the
efficacy and safety of Lixisenatide in patients with type 2 diabetes
insufficiently
controlled with insulin glargine and metformin.
Study primary objectives
The primary objective of this study is to assess the effects on glycemic
control of
lixisenatide in comparison to placebo as an add-on treatment to insulin
glargine and
metformin over a period of 24 weeks.
Study secondary objectives
The secondary objectives are
= To assess the effects of lixisenatide (AVE0010) on the percentage of
patients
reaching HbAlc <7 % and < or = 6.5 %, on plasma glucose (fasting, post-
prandial during a standardized meal challenge test, 7-point self monitored
profiles), body weight, insulin glargine doses.
= To evaluate lixisenatide safety and tolerability as add on treatment to
insulin
glargine and metformin.
= To assess the impact of lixisenatide on treatment satisfaction using the
Diabetes Treatment Satisfaction Questionnaire (state) (DTSQs) in the
participating countries where it is validated. 11 Condition Intervention Phase
Type 2 Diabetes Mellitus Drug: lixisenatide (AVE0010) Phase III
Drug: placebo
Drug: insulin glargine (HOE901)
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Study Type: Interventional
Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver,
Investigator, Outcomes Assessor), Placebo Control,
Parallel Assignment, Efficacy Study
Primary Outcome Measures:
= Change in glycated hemoglobin (HbAlc) (time frame: 24 weeks,
designated as safety issue: no)
Secondary Outcome Measures:
= Percentage of patients with HbAlc <7 %, < or = 6.5 % (time frame: 24 weeks,
designated as safety issue: no)
= Change in postprandial plasma glucose (time frame: 24 weeks,
designated as safety issue: no)
= Change in fasting plasma glucose (time frame: 24 weeks,
designated as safety issue: no)
= Change in 7-point Self Monitored Plasma Glucose (SMPG) profiles (time
frame: 24 weeks, designated as safety issue: no)
= Change in body weight (time frame: 24 weeks, designated as safety issue: no)
= Change in insulin glargine dose (time frame: 24 weeks,
designated as safety issue: no)
= Percentage of patients requiring rescue therapy during the double-blind
period
(time frame: 24 weeks, designated as safety issue: no)
= Change in treatment satisfaction score (DTSQ questionnaire, time frame: 24
weeks, designated as safety issue: no)
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Estimated Enrolment: 290
Arms Assigned interventions
Lixisenatide: Experimental Drug: lixisenatide (AVE0010)
124-week treatment with lixisenatide once solution for subcutaneous injection
daily on top of insulin glargine (both
;injected in the morning within 1 hour Drug: insulin glargine (HOE901)
prior to breakfast) and metformin (at solution for subcutaneous injection
least 1.5g/day)
;Placebo: Placebo Comparator Drug: placebo
24-week treatment with placebo once solution for subcutaneous injection
,daily on top of insulin glargine (both
injected in the morning within 1 hour Drug: insulin glargine (HOE901)
prior to breakfast) and metformin (at solution for subcutaneous injection
least 1.5g/day)
Detailed Description
The study will comprise 3 periods:
= An up-to 14-week screening period, which includes an up to 2-week screening
phase and a 12-week run-in phase with introduction and titration of insulin
glargine on top of metformin +/-TZDs.
= At the end of the run-in phase, patients whose HbA1 c (centralized assay) is
>
or = 7% and < or = 9% and whose mean fasting SMPG calculated from the
self measurements for the 7 days prior to visit 12 (week -1) is less than or
equal to 126 mg/dl (7.0 mmol/I), will enter a 24-week double-blind randomized
treatment period comparing lixisenatide to placebo (on top of insulin glargine
+ metformin +/-TZDs).
= A 3 day-safety follow up period.
Maximum duration of 39 weeks 7 days
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Eligibility
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
5
Inclusion criteria:
At screening
= Patients with type 2 diabetes mellitus, as defined by WHO (fasting plasma
glucose > or = 7 mmol/L (126mg/dL) or 2 hours postprandial plasma glucose
10 > or = 11.1 mmol/L (200 mg/dL), diagnosed at least 1 year before the
screening visit
= For at least 3 months: treatment with a stable dose of metformin > or = 1.5
g/day or combination of stable doses of metformin > or = 1.5 g/day with
sulfonylureas (SUs) (to be stopped at visit 1) and/or Thiazolidinediones
(TZDs)
= Glycated hemoglobin (HbA1 c) > or = 7.0 and < or = 10%
At the end of the run in phase and before randomization:
= HbA1c>or=7.0and<or=9%
= Mean fasting Self Monitored Plasma Glucose (SMPG) calculated from the self
measurements for the 7 days prior to visit 12 (week -1) is less than or equal
to
126 mg/dII (7.0 mmol/I)
Exclusion criteria:
At screening:
= Pregnancy or lactation
= Women of childbearing potential with no effective contraceptive method.
= Type 1 diabetes mellitus
= Metformin not at a stable dose of at least 1.5 g/day for at least 3 months
prior
to the screening visit.
= Use of oral or injectable antidiabetic or hypoglycemic agents other than
metformin, sulfonylurea and thiazolidinediones within 3 months prior to the
time of screening, use of weight loss drugs if not at a stable dose for at
least 3
months prior to the screening visit.
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= History of hypoglycemia unawareness.
= History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy,
stomach/gastric surgery, inflammatory bowel disease
= History of metabolic acidosis, including diabetic ketoacidosis within 1 year
prior to screening
= Hemoglobinopathy or hemolytic anemia, blood or plasma products transfusion
within 3 months prior to the time of screening
= Within the last 6 months prior to screening: history of myocardial
infarction,
stroke, or heart failure requiring hospitalization
= Known history of drug or alcohol abuse within 6 months prior to the time of
screening
= Uncontrolled or inadequately controlled hypertension at the time of
screening
with a resting systolic or diastolic blood pressure >180 mmHg or >110 mmHg,
respectively
= Use of systemic glucocorticoids (excluding topical application or inhaled
forms) for one week or more within 3 months prior to the time of screening
= Use of any investigational drug within 3 months prior to screening
= Renal impairment defined with serum creatinine >1.4 mg/dL in women and
>1.5 mg/dL in men
= History of hypersensitivity to insulin glargine or to any of the excipients
= Clinically relevant history of gastrointestinal disease associated with
prolonged nausea and vomiting, including (but not limited to): gastroparesis,
unstable (i.e worsening) and not controlled (i.e prolonged nausea and
vomiting) gastroesophageal reflux disease requiring medical treatment, within
6 months prior to the time of screening
= Any previous treatment with lixisenatide (e.g. participation in a previous
study
with lixisenatide)
= Allergic reaction to any GLP-1 receptor agonist in the past (e.g. exenatide,
liraglutide) or to metacresol
Additional exclusion criteria during or at the end of the run-in phase before
randomization:
= Informed consent withdrawal (patient who is not willing to continue or fails
to
return)
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= Mean fasting SMPG calculated from the self-measurements for the 7 days
prior to visit 12 (week -1) is >126 mg/dI (7.0 mmol/I)
= HbAlc measured at visit 12 (week -1) is <7% or >9 %,
= Amylase and/or lipase >3 times the upper limit of the normal laboratory
range
at visit 12 (week -1)
The above information is not intended to contain all considerations relevant
to a
patient's potential participation in a clinical trial.
