Note: Descriptions are shown in the official language in which they were submitted.
CA 02685636 2009-11-13
Sanofi Aventis Deutschland GmbH DE2009/199 Dr. FI
Method of treatment of diabetes type 2 comprising add-on therapy to 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 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. However, control diabetes mellitus type 2 in obese patients by
metformin 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 or/and a pharmaceutically acceptable
salt thereof, and
(b) metformin or/and a pharmaceutically acceptable salt thereof,
to a subject in need thereof.
The compounds of (a) and (b) 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:
CA 02685636 2009-11-13
2
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 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).
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 once a day (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.
CA 02685636 2009-11-13
3
In the present invention, a liquid composition comprising desPro36Exendin-4(1-
39)-
Lys6-NH2 or/and a pharmaceutically acceptable salt thereof may be employed.
The
skilled person knows liquid compositions of AVE0010 suitable for parenteral
administration. A liquid composition of the present invention 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 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 of the present invention 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.
The liquid composition of the present invention 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 CaCI2. 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 non proprietary name of 1,1-dimethylbiguanide
(CAS
Number 657-24-9). In the present invention, the term "metformin" includes any
pharmaceutically acceptable salt thereof.
CA 02685636 2009-11-13
4
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 1.0 g/day
or 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
administration of metformin.
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 and
AVE0010.
Metformin and AVE0010 may be administered within a time interval of 24 h.
Metformin and AVE0010 each may be administered in a once-a-day-dosage.
Metformin and AVE0010 may be administered by different administration routes.
Metformin may be administered orally, and AVE0010 may be administered
subcutaneously.
The subject to be treated by the method of the present invention suffering
from
diabetes type 2 may be an obese subject. In the present invention, an obese
subject
may have a body mass index of at least 30.
The subject to be treated by the method of the present invention may have a
HbA1 c
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 alone, for instance with a dose of at least 1.0
g/day
metformin or at least 1.5 g/day metformin for 3 months. In the present
invention, a
CA 02685636 2009-11-13
subject the diabetes type 2 of which is not adequately controlled may have a
HbA1 c
value in the range of 7 % to 10%.
Another aspect of the present invention is a pharmaceutical combination
comprising
5 (a) desPro36Exendin-4(1-39)-Lys6-NH2 or/and a pharmaceutically acceptable
salt thereof, and
(b) metformin or/and a pharmaceutically acceptable salt thereof.
Preferably, the combination of the present invention is for treatment of
diabetes
mellitus type 2.
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) and
(b) 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, and
(b) 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 and metformin in
separate formulations, as described herein.
The invention is further illustrated by the following example.
CA 02685636 2009-11-13
6
Example
24-week study comparing lixisenatide (AVE0010) to sitagliptin as add-on to
metformin in obese type 2 diabetic patients younger than 50
Subject of the example is a randomized, double-blind, double-dummy, 2-arm
parallel-group, multicenter, 24-week study comparing the efficacy and safety
of
lixisenatide (AVE0010) to sitagliptin (CAS Number 486460-32-6) as add-on to
metformin in obese type 2 diabetic patients younger than 50 years and not
adequately controlled with metformin. Sitagliptin is an antidiabetic drug,
acting as an
inhibitor of dipeptidyl peptidase 4 (DPP4) resulting in enhanced level of
Glucagon-
Like Peptide 1, thereby reducing blood glucose levels in diabetic patients.
Study Primary Objectives
The primary objective of this study is to assess the efficacy of lixisenatide
on a
composite endpoint of glycemic control (HbAlc) and body weight in comparison
to
sitagliptin as an add-on treatment to metformin over a period of 24 weeks in
obese
type 2 diabetic patients younger than 50.
Study Secondary Objectives are assessment of the effects of lixisenatide on:
. Absolute changes in HbA1 c and body weight
Fasting plasma glucose
Plasma glucose, insulin, C peptide, glucagon and proinsulin during a 2-hour
standardized meal test
Insulin resistance assessed by HOMA-IR
. Beta cell function assessed by HOMA-beta
To assess lixisenatide safety and tolerability
To assess lixisenatide PK using the population PK approach and to assess
anti-lixisenatide antibody development.
Specific vulnerable populations:
Women of child-bearing potential using contraception.
CA 02685636 2009-11-13
7
Inclusion criteria
Patients (male and female) with type 2 diabetes mellitus, as defined by WHO
(21),
diagnosed for at least 1 year at the time of screening visit, insufficiently
controlled
with metformin at a stable dose of at least 1.5 g/day, for at least 3 months
prior to the
2
screening visit. Patients with obesity (BMI >_ 30kg/m ) and aged from 18 years
to less
than 50 years.
Exclusion criteria
. HbAlc <7.0% or HbAlc >10% at screening
. Type 1 diabetes mellitus
. Pregnancy or lactation
. Women of childbearing potential with no effective contraceptive method
. Fasting Plasma Glucose at screening >250 mg/dL (>13.9 mmol/L)
. Weight change of more than 5 kg during the 3 months preceding the
screening visit
. 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 or receipt of blood or plasma products
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
. Any clinically significant abnormality identified on physical examination,
laboratory tests, ECG or vital signs at the time of screening that in the
judgment of the investigator or any sub investigator would preclude safe
completion of the study or constrains efficacy assessment such as major
systemic diseases, presence of clinically significant diabetic retinopathy or
presence of macular edema likely to require laser treatment within the study
period
CA 02685636 2009-11-13
8
= Uncontrolled or inadequately controlled hypertension at the time of
screening
with a resting systolic or diastolic blood pressure >180 mmHg or >110
mmHg, respectively
= Laboratory findings at the time of screening:
- Amylase and/or lipase >3 times the upper limit of the normal laboratory
range
- Total bilirubin: >1.5 times the upper limit of the normal laboratory range
(except in case of Gilbert's syndrome)
- Hemoglobin <11 g/dL and/or neutrophils <1,500/mm3 and/or platelets
<100,000/mm3
- Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody
- Positive serum pregnancy test in females of childbearing potential
= Use of other oral or injectable antidiabetic or hypoglycemic agents than
metformin (e.g., sulfonylurea, alpha glucosidase inhibitor, thiazolidinedione,
exenatide, DPP-IV inhibitors, insulin etc.) within 3 months prior to the time
of
screening
= Unstable diet or unstable anti-obesity treatment within 3 months prior to
the
time of screening
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
Clinically relevant history of gastrointestinal disease associated with
prolonged nausea and vomiting, including, but not limited to gastroparesis
and 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-agonist in the past (e.g. exenatide,
liraglutide)
or to metacresol
. History of a serious hypersensitivity reaction to sitagliptin.
= Moderate or severe renal impairment (creatinine clearance inferior to 50
ml/min)
CA 02685636 2009-11-13
9
Duration of study period per subject
Maximum duration of 27 weeks 7 days (3-week screening + 24-week double-
blind,
double-dummy, active-controlled treatment + 3-day follow-up)
INVESTIGATIONAL PRODUCTS
INN Compound code Pharmaceutical form Route of
administration
Lixisenatide VE0010 injection subcutaneous
Sitagliptin capsules capsules
STUDY ARMS Number of arms: 2
rm Label Arm description Arm type
Lixisenatide Injection of lixisenatide once a day in the Experimental
morning within 1 hour prior to breakfast
(first 2 weeks of double-blind period:
titration 10 to 15 pg, then 15 to 20 pg) and
one capsule of sitagliptin placebo intake in
he morning or without food. On top of
metformin background therapy.
Sitagliptin One capsule of sitagliptin intake in the Active
morning with or without food and Calibrator/Comparator
lixisenatide matched placebo injection
once a day in the morning within hour
prior to breakfast. On top of metformin
background therapy.
CA 02685636 2009-11-13
ENDPOINTS
Primary Endpoint(s): Time frame for evaluation
Percentage of patients with HbA1 c values <7% 24 weeks
ND a weight loss of at least 5% of baseline body
eight
Secondary Endpoint(s): Time frame for evaluation
bsolute change in HbAlc values 4 weeks
Percentage of patients with HbA1 c values <_ 6.5% 24 weeks
bsolute change in body weight 4 weeks
Change in fasting plasma glucose 4 weeks
Change in plasma glucose and in (3-cell function 4 weeks
during a test meal
hange in insulin resistance assessed by HOMA-IR 4 weeks
Change in R-cell function assessed by HOMA-0 4 weeks
Percentage of patients requiring rescue therapy 24 weeks
during the double-blind period
5
