NZ715144B2 - Insulin glargine/lixisenatide fixed ratio formulation - Google Patents

Abstract

The present invention refers to a pharmaceutical composition comprising (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) insulin glargine or/and a pharmaceutically acceptable salt thereof, wherein the compound (b) and compound (a) are present in a fixed ratio. A particular embodiment of the invention is directed at the use of compounds (a) and (b) in the manufacture of a medicament for treating diabetes mellitus type 2 in a subject as add-on to treatment with metformin and/or a pharmaceutically acceptable salt thereof, where compound (b) is present in a concentration of 100 U/ml, and compound (a) is present in a concentration of 50 µg/ml. embodiment of the invention is directed at the use of compounds (a) and (b) in the manufacture of a medicament for treating diabetes mellitus type 2 in a subject as add-on to treatment with metformin and/or a pharmaceutically acceptable salt thereof, where compound (b) is present in a concentration of 100 U/ml, and compound (a) is present in a concentration of 50 µg/ml.

Description

lnsulin glargine/lixlsenatide fixed ratio formulation Description Subject of the present invention is a pharmaceutical composition comprising (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) insulin glarglne or/and a ceutically acceptable salt thereof, wherein the compound (b) and compound (a) are present in a ratio of about 1.6 to about 2.4 U of compound (b) per pg of compound (a). in a y person the release of insulin by the as is strictly coupled to the concentration of blood glucose. An increased level of blood glucose, as appears after meals, is y counterbalanced by a respective increase in insulin secretion. In fasting condition the plasma insulin level drops to a basal value which is sufficient to ensure the continuous supply of glucose to n- sensitive organs and tissues and to keep the hepatic glucose production at a low level at night.

In contrast to es type 1, there is not generally a lack of insulin in diabetes type 2 but in many cases, particularly in progressive cases, the treatment with insulin is regarded as the most suitable therapy, if required in combination with orally administered anti—diabetic drugs.

An increased glucose level _in the blood over. several years without initial symptoms represents a icant health risk. it could clearly be shown by the scale DCCT study in the USA (the iabetes Control and Complications Trial Research Group (1993) N. Engl. J. Vled. 329, 6) that chronically increased levels of blood glucose are a main reason for the development of diabetes complications. Examples for es complications are micro and macrovascular damages that possibly manifest themselves in retinopathies, nephropathies or neuropathies and lead to blindness, renal failure and the loss of extremities and are accompanied by an increased risk of cardiovascular diseases. It can thus be concluded that an improved therapy of diabetes primarily has to aim keeping blood glucose in the physiological range as closely as possible.

A particular risk exists for overweight patients suffering from diabetes type 2, e.g. patients with a body mass index (BMI) 230. in these patients the risks of diabetes overlap with the risks of overweight, leading e.g. to an increase of cardiovascular diseases ed with diabetes type 2 patients being of a normal weight. Thus, it is particularly necessary to treat diabetes in these patients while reducing the eight.

Metformin is a biguanide hypoglycemic agent used in the treatment of non- lnsulin-dependent diabetes mellitus (diabetes mellitus type 2) not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. min 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.

The compound desProaBExendin-élfl—39)-Lys6—NH2 10, lixisenatide) is a derivative of Exendin—4. Lixisenatide is disclosed as SEQ lD N0293 in wo 01/041562 :xendins are a group of es which can lower blood e concentration.

The Exendin analogue natide is characterised by C—terminal truncation of the native -xendin—4 sequence. _ixisenatide comprises six inal lysine residues not present in :xendin-4.

In the context of the present invention, lixisenatide includes pharmaceutically able salts thereof. The person skilled in the art knows ceutically 3O acceptable salts of lixisenatide. A preferred pharmaceutically acceptable salt of lixisenatide employed in the present invention is acetate. insulin ne is 318—328—Ii-Arg human n, an analogue of human insulin, with further tution of asparagine in on A21 by glycine. insulin glargine is also termed Giy(A21)-=Arg(BB1)—Arg(l332)-human insulin. in the present invention, insulin ne includes pharmaceutically acceptable salts f. insulin glargine is disclosed in US 5 656 722.

Lantus® is an insulin product containing insulin glargine providing 24 hours basal insulin supply after single dose subcutaneous injection.

A dose of 100 U insulin glargine requires injection of 1 m- Lantus® U100, each ml. ® U100 contains 100 U insulin glargine. 100 U insulin glargine correspond to 3.6378 mg insulin glargine. discloses an on—site mixture comprising a fixed concentration of insulin glargine and a variable tration of lixisenatide. This document also discloses an exemplary on—site mixed preparation ning 100 U/mL insulin glargine and 66,67 ug/mL (or 800/300*25 ug/m _) iixlsenatide, 60.6 pg/mL (or 800/330*25 ug/mL) iixlsenatide, 55.56 ug/mL (or 800/360*25 pg/mL) lixisenatide, 51.28 ug/mL natide (or 800/390*25 ug/m_ lixisenatide), 47.62 pg/mL (or 800/420*25) lixisenatide, 44.44 ug/ml. (or 800/450*25 pg/mL) lixisenatide, 41.67 ug/mL (or 800/480*25 pg/mL) lixisenatide or 39.22 ug/mL (or 800/510*25 ug/mL) lixisenatide. in :xampie 1 of the present ion, the efficacy of a formulation comprising 100 U/mL insulin glargine and 50 ug/mi natide was tested in comparison with a formulation comprising 100 U/ml insulin glargine in diabetes type 2 patients. it has been demonstrated that in the combination group (treated with the insulin glargine/lixisenatide fixed ratio formulation) the final daily dose at the end of the treatment period was reduced compared with the group receiving the formulation to reach a fasting self-monitored plasma glucose concentration between 280 and S100 mg/dL. in the combination group 0 % received a dose of >60 U/30 pg, 3O and 42.2% received a dose of >40 U/20 ug and £60 U/30 pg. in the control group 28.4% of the ts received a dose of >40 U/20 μg and ≤ 60 U/30 μg, and 16.7% of the patients ed a dose of >60 U/30 µg. In the combination group, 14.3% of the patients received a dose <20 U/10 µg, whereas only 9.9 % of the control patients received this dose (Table 6).

Furthermore, treatment with insulin glargine/lixisenatide fixed ratio combination significantly improved postprandial glycemic l in comparison to insulin glargine as shown by the s for the 2-hour PPG ment and for 2-hour glucose excursion. In addition, patients treated with insulin glargine/lixisenatide fixed ratio ation had a statistically significant greater decrease in average 7-point self-monitored plasma glucose (SMPG) profile compared with patients d with n glargine.

A statistically significant difference in the body weight change from baseline to week 24 was found between the 2 treatment groups: body weight decreased in the insulin glargine/lixisenatide fixed ratio combination group and increased in the insulin glargine group.

A higher tage of patients in the combination group reached target HbA1c ≤ 6.5% (71.9% versus 64.6%) or <7 % (84.4% versus 78.3 %) as compared with the insulin glargine group (Table 8).

In summary, the insulin glargine/lixisenatide fixed ratio combination results in an improvement of glycemic control and body weight by a reduced dose of insulin glargine, compared with insulin glargine alone. This demonstrates the superiority of an insulin glargine/lixisenatide fixed ratio combination versus insulin glargine.

Example 2 bes a randomized, 30 week, active-controlled, open-label, 3- treatment arm, parallel-group multicenter study comparing the efficacy and safety of insulin glargine/lixisenatide fixed ratio combination of the t invention to insulin glargine alone and to lixisenatide alone on top of metformin in patients with type 2 diabetes mellitus (T2DM).

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. 17793690_1 (GHMatters) P41292NZ00 In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as ises” or “comprising” is used in an inclusive sense, i.e. to y the presence of the stated features but not to preclude the presence or on of further features in various ments of the invention.

One aspect of the present ion is use of (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) insulin glargine or/and a ceutically acceptable salt thereof, in the cture of a pharmaceutical composition for the treatment of diabetes mellitus type 2 in a subject as add-on to treatment with metformin and/or a pharmaceutically acceptable salt thereof, wherein the compound (b) is present in a concentration of 100 U/ml, and compound (a) is present in a concentration of 50 µg/ml.

Also described is a pharmaceutical composition comprising (a) Lixisenatide (desPro36Exendin-4(1-39)-Lys6-NH2) or/and a pharmaceutically acceptable salt thereof, and (b) insulin glargine or/and a ceutically acceptable salt f, wherein the compound (b) and compound (a) are present in a ratio of about 1.6 to about 2.4 U of compound (b) per µg of compound (a).

Compound (b) and compound (a) can also be present in a ratio of about 1.8 to about 2.2 U of compound (b) per µg of compound (a). Compound (b) and compound (a) can also be present in a ratio of about 1.9 to about 2.1 U of compound (b) per µg of compound (a). Compound (b) and compound (a) can also be present in a ratio of about 2 U of compound (b) per µg of compound (a).

The concentration ratio of compound (b) to compound (a) in the pharmaceutical composition of the present invention is a fixed ratio. 17793690_1 (GHMatters) P41292NZ00 In the present invention, compound (a) and compound (b) are provided in a single composition in a pre-determined fixed ratio. Also within the scope of the present invention are two separate compositions, the first composition comprising compound (a) and the second composition comprising compound (b), to be administered to a patient in need thereof as d herein, in a fixed ratio as defined .

In the ition of the present invention, the concentration of compound (a) can be in the range of 40 - 60 µg/ml. The concentration ratio of compound (b) to compound (a) can be in the range of 1.6 to 2.4 U/µg, 1.8 to 2.2 U/µg, 1.9 to 2.1 U/µg or about 2 U/µg.

In the composition of the present invention, the concentration of nd (b) can be in the range of 64 -144 U/ml, 72-132 U/ml, 76-126 U/ml or 80 -120 U/ml.

In the composition of the present invention, the concentration of compound (a) 17793690_1 (GHMatters) P41292NZ00 can be in the range of 40 — 60 pg/ml, and the concentration of compound (b) can be in the range of 64 ~144 U/ml, 72—132 U/ml, 76-126 U/ml or 80 —120 U/ml.

In the composition of the present invention, the concentration of compound (a) can be in the range of 45 - 55 pg/ml. The concentration ratio of compound (b) to compound (a) can be in the range of 1.6 to 2.4 U/pg, 1.8 to 2.2 U/pg, 1.9 to 2.1 U/ug or about 2 U/pg. in the composition of the present invention, the concentration of compound (b) can be in the range of 72 —132 U/ml, 81 ~12] U/ml, 85.5 -115.5 U/ml, or 90 ~11O U/ml. in the composition of the present invention, the tration of compound (a) can be in the range of 45 - 55 pg/ml, and the concentration of compound (b) can be in the range of 72 — 132 U/ml, 81 -121 U/ml, 85.5 —115.5 U/ml, or 90 -110 U/ml.

In the pharmaceutical composition, the concentration of compound (a) can also be about 50 ug/m_. The tration ratio of compound (b) to compound (a) can be in the range of 1.6 to 2.4 U/ug, 1.8 to 2.2 U/ug, 1.9 to 2.1 U/pg or about 2 U/pg. The concentration of compound (b) can be in the range of 80 - 120 U/ml, 90 -1_10 U/ml, 95 -105 U/ml, or can be about 100, U/ml.

In particular, in the composition of the present invention the tration of compound (a) is about 50 ug/ml, and the concentration of compound (b) is about 100 U/ml.

The pharmaceutical composition ably is not an on-site mixed composition or formulation. The on-site mixed composition or formulation is ted “on— site”, for example shortly before administration. In this context, an on—site mixed composition or formulation can be a composition or formulation prepared from at least two separate compositions, each comprising at least one of lixisenatide and n glargine. in particular, an on-site mixed formulation or composition is a composition prepared from two te compositions, the first composition comprising natide and insulin glargine, and the second composition sing insulin glargine. More particular, the on—site mixed composition or formulation can comprise a fixed volume of the first composition and a variable volume of the second ition.

If the pharmaceutical composition compr'ses compound (a) in a concentration range of 40 to 60 pg/ml, the concentration of compound (a) preferably is not a concentration selected from 55.56 pg/m_, 51.28 pg/m_, 47.62 pg/m_, 44.44 pg/mL, and 41,67 pg/mL. In the concentration range of 40 to 60 ug/ml, the concentration of compound (a) preferably is not a concentration selected from 800/360*25 ug/mL, 800/390*25 pg/mL, 800/420*25 ug/mL, 800/450*25 ug/mL, and 800/480*25 pg/mL.

If the pharmaceutical composition comprises compound (a) in a tration range of 45 to 55 ug/ml, the concentration of compound (a) is preferably not a tration selected from 51.28 pg/m and 47.62 pg/mL. in the concentration range of 45 to 55 pg/ml, the concentrat'on 0' compound (a) preferably is not a concentration selected from 800/390*25 Ibig/m. and 800/420*25 pg/mL.

The composition of the present invention can be used for the treatment of diabetes mellitus typet or/and 2 patients, or/and for the treatment of conditions associated with diabetes type diabetes us type 1 or/and 2.

In particular the composition of the present invention can be used for the treatment of diabetes mellitus type 2 patients, or/and for the treatment of conditions associated with es type diabetes mellitus type 2. Such conditions include a decrease of glucose tolerance, an increased postprandial plasma glucose tration, an increase in fasting plasma glucose concentration, or/and an increased HbA1C value, compared for example with persons not suffering from diabetes type 2.

The composition of the present invention can be used in glycemlc control in diabetes type 2 patients. As demonstrated by Example 1 of the present invention, the composition as described herein can be used for improving glycemic control. In the present invention, vement of glycemic l” or “glycemic control” in particular refers to improvement of glucose tolerance, improvement of postprandial plasma glucose concentration, improvement of fasting plasma glucose concentration, or/and improvement of the l-bA1C value.

In particular, improvement of glucose tolerance includes improvement of the postprandial plasma glucose tration, improvement of the postprandial plasma glucose excursion or/and improvement of fasting plasma glucose concentration. More particular, improvement of glucose tolerance includes improvement of the postprandial plasma glucose tration.

In particular, improvement of postprandial plasma glucose concentration is ion of the postprandial plasma glucose concentration. Reduction means in particular that the plasma glucose concentration reaches normoglycemic values or at least approaches these values.

In particular, improvement of postprandial plasma glucose excursion is reduction of the andial plasma e excursion. eduction means in particular that the plasma glucose excursion reaches normoglycemic values or at least ches these . ln particular, improvement of fasting plasma glucose concentration is reduction of the g plasma glucose concentration. ion means in particular that the plasma glucose tration reaches normoglycemic values or at least approaches these values. 3O In particular, improvement of the HbA1C value is reduction of the -|b,L\1C value.

Reduction of the HbA1C value in particular means that the :bA1C value is reduced below 6.5 % or 7 %, for example after treatment for at least one month, at least 1010 two months, at least three months, at least four months, at least five months, at least six months or at least one year.

The pharmaceutical composition of the present invention may be administered as add—on to the ent with metformin or/and a pharmaceutically acceptable salt thereof. lVletformin is the international prietary name of 1,1— ylbiguanide (CAS Number 657-24—9). ln the present invention, the term "metformin" includes any ceutically acceptable salt thereof. ln the t invention, metformin may be administered orally. The skilled person knows formulations of metformin suitable for ent of diabetes type 2 by oral administration. Metformin may be administered to a patient in need thereof, in an amount sufficient to induce a therapeutic effect. 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. Metformin may be formulated with suitable pharmaceutically acceptable rs, adjuvants, or/and auxiliary nces. in the present invention, the terms "add—on", "add-on treatment", "add-on therapy" and “on top of” relate to treatment of diabetes mellitus type 2 with the metformin and the composition of the present invention, as described herein.

The composition of the present invention and metformin may be administered by different administration routes. Metformin may be administered orally, and the composition of the present invention may be administered parenterally.

The patient to be treated by the composition of the present invention may be a patient suffering from diabetes type 2.

The patient to be treated by the composition of the present invention ing from es type 2 may be a patient suffering from diabetes type 2, wherein diabetes type 2 is not adequately controlled by treatment with metformin alone, for example by treatment with metformin for at least 2 or at least 3 months, for e with a dose of at least 1.0 g/day or at least 1.5 g/day of metformin. ln particular, the diabetes type 2 is not adequately controlled by treatment with 1111 metformin alone at the onset of treatment with the composition of the t invenfion.

The patient to be treated by the composition of the present invention suffering from diabetes type 2 may be a patient suffering from diabetes type 2, wherein diabetes type 2 is not adequately controlled by treatment with insulin glargine alone, for example by ent with n glargine for at least 2 or at least 3 months. In particular, the diabetes type 2 is not adequately controlled by treatment with insulin glargine alone at the onset of treatment with the composition of the t invention.

The patient to be d by the ition of the present invention suffering from diabetes type 2 may be a patient ing from diabetes type 2, wherein diabetes type 2 is not adequately controlled by treatment with lixisenatide alone, for example by treatment with lixisenatide for at least 2 or at least 3 months. in particular, the diabetes type 2 is not adequately controlled by treatment with lixisenatide alone at the onset of treatment with the composition of the present The patient to be d by the composition of the present invention suffering from diabetes type 2 may be a patient suffering from diabetes type 2, wherein diabetes type 2 is not adequately controlled by treatment with metformin and insulin glargine alone, or with metformin and lixisenatide alone, for example by treatment for at least 2 or at least 3 months. in particular, the diabetes type 2 is not adequately controlled by treatment with metformin and n glargine alone, or with metformin and lixisenatide alone at the onset of treatment with the composition of the present invention. in the present invention, a patient the diabetes type 2 of which is not adequately controlled if at least one physiological parameter describing blood glucose tration (i.e. the HbA’lc value, the postprandial plasma glucose concentration, the postprandial plasma glucose excursion, or/and the fasting plasma glucose concentration) exceeds normoglycemic values, as described 1212 herein. in particular, a patient the diabetes type 2 of which is not adequately controlled may have (i) a -le1c value in the range of 7 % to 10 % or even larger, (ii) a postprandial glucose excursion, in particular a 2—hour postprandial glucose excursion, of at least 2 mmol/L, (iii) a postprandial plasma glucose concentration, in particular a 2-hour postprandial glucose concentration, of at least 10 mmol/L, or/and (iv) a fasting plasma glucose of at least 7.0 mmol/, or 8.0 mmol/L.

The patient to be treated by the composition of the present ion suffering from diabetes type 2 may be an obese patient. in the present ion, an obese patient may have a body mass index of at least 30 kg/mz, at least 31 kg/mz, at least 32 kg/m2 or at least 33 kg/mz.

The patient to be treated by the ition of the present invention suffering from diabetes type 2 may have a normal body weight. In the present invention, a t having normal body weight may have a body mass index in the range of 17 kg/m2 to 25 kg/mz, 17 kg/m2 to <30 kg/m2 or <30 kg/rnz.

The patient to be treated by the composition of the present invention may be an adult patient. The patient may have an age of at least 18 years of may have an age in the *ange of 18 to 80 years, of 18 to 50 years, or 40 to 80 years, or 50 to 60 years. he patient may be at least 50 years old. The patient may be younger than 50 years.

The patient to be treated by the composition of the present invention may be a t who does not receive an antidiabetic treatment, for instance by insulin or/and related compounds, metformin or G_P-1 agonists such as lixisenatide. In particular, the t to be d does not receive a GLP-1 receptor t or/and an insulin.

The t to be treated by the composition of the present invention may suffer from diabetes mellitus type 2 for at least 1 year or at least 2 years. in particular, in the diabetes type 2 patient, diabetes mellitus type 2 has been diagnosed at 1313 least 1 year or at least 2 years before onset of y by the composition of the present invention.

The diabetes type 2 patient may have a -le10 value of at least about 9 %, at least 8 %, at least about 7,5 %, or at least 7.0 % at the onset of the treatment with the composition. The patient may also have a l-le1C value of about 7 % to about 10 % at the onset of the ent with the composition. Example ’1 of the present invention demonstrates that treatment by natide results in a reduction of the l-rle1C value in es type 2 patients.

In yet another aspect of the present invention, the composition as described herein can be used for improving the l-~le1C value in a patient suffering from diabetes type 2, as described .

In yet another aspect of the present invention, the composition as described herein can be used for improving glucose tolerance in a patient suffering from diabetes type 2, as described herein. Example 1 of the present ion demonstrates an improved 2-hour glucose excursion. in yet another aspect of the present invention, the composition as described herein can be used for improving postprandial plasma glucose concentration in a patient suffering from diabetes type 2, as described herein. Example 1 of the present invention demonstrates an improved 2—hour postprandial glucose concentration. in yet another aspect of the present invention, the composition as described herein can be used for improving postprandial plasma glucose excursion, in ular the 2—hour postprandial glucose excursion, in a patient suffering from es type 2, as described herein.

In yet another aspect of the present ion, the composition as described herein can be used for improving fasting plasma glucose tration in a patient suffering from diabetes type 2, as described herein. 1414 In yet r aspect of the present ion, the composition as described herein can be used for improving average t SMPG profile. Example 1 of the present invention demonstrates an ed average 7-point SMPG profile by administration of the composition of the present invention to diabetes type 2 patients. Self-monitored plasma glucose (SMPG)”, as used , is in particular the nt Self Monitored Plasma Glucose”. nt Self Monitored Plasma Glucose” in particular refers to the measurement of plasma glucose seven times a day and calculation of the average plasma glucose concentration therefrom.

The “7—point Self Monitored Plasma Glucose” value is in particular an average plasma glucose concentration including fasting and postprandial conditions. in particular, measurements of plasma glucose concentration are performed pre- breakfast, post—breakfast (e.g. 2-hour post-breakfast), pre—lunch, post-lunch (e.g. 2-hour post—lunch), pre—dinner, post—dinner (e.g. 2-hour post-dinner) and at bed— time (see also Figure 3). The ent by the combination of the present invention, as described herein, can improve the self-monitored plasma glucose. in yet another aspect of the present invention, the composition as described herein can be used for improving body weight in a patient suffering from diabetes type 2, as described herein. Example 1 of the present invention demonstrates in improvement of body weight by administration of the composition of the present ion. in the t invention, normoglycemic values are blood glucose concentrations of in particular 60 — 140 mg/dl (corresponding to 3,3 bis 7,8 mM/_). This range refers in particular to blood e concentrations under fasting conditions or/and postprandial conditions.

The diabetes type 2 patient may have a 2—hour postprandial plasma glucose concentration of at least 10 mmol/L, at least 12 mmol/L, at least 13 mmol/L, at least 14 mmol/_, at least 15 mmol/L, at least 16 mmol/L, or at least 17 mmol/L at the onset of the treatment with the composition of the present invention. These plasma glucose concentrations exceed normoglycemic concentrations. 1515 The es type 2 patient may have a glucose excursion (in particular a 2—hour postprandial glucose ion of at least 2 mmol/L, at least 3 mmol/L, at least 4 mmol/L, at least 5 mmol/L, at least 5.5 mmol/_, at least 6 mmol/L, at least 6.5 mmol/L, or at least 7 mmol/_ at the onset of the treatment with the composition of the present invention. in the present ion, the glucose excursion is in particular the difference of the 2-hour postprandial plasma glucose concentration and the plasma glucose concentration 30 minutes prior to a meal test.

“Postprandial” is a term that is well known to a person d in the art of diabetology. The term “postprandial” describes in particular the phase after a meal or/and exposure to glucose under experimental conditions. in a healthy person this phase is characterised by an increase and uent decrease in blood glucose concentration. The term “postprandial" or randial phase” typically ends up to 2 h after a meal or/and exposure to glucose.

The diabetes type 2 patient as disclosed herein may have a g plasma glucose concentration of at least 7 mmol/-, at least 8 mmol/L, at least 9 mmol/L, at least 10 mmol/L, or at least 11 mmol/L at the onset of the treatment with the composition of the present invention. These plasma glucose concentrations exceed normoglycemic concentrations at the onset of the treatment with the ition of the present invention.

The diabetes type 2 patient as disclosed herein may have a self—monitored plasma glucose concentration of at least 8 mmol/L, at least 9 mmol/L, at least 10 mmol/L, or at least 11 mmol/L at the onset of the treatment with the composition of the present invention.

In the present ion, the composition as described herein may be administered to a patient in need thereof, in an amount sufficient to induce a therapeutic effect. in the present invention, the composition as bed herein may comprise at least one of suitable pharmaceutically acceptable carriers, adjuvants, or/and ary substances. 1616 The composition as described herein may be administered parenterally, e.g. by injection (such as by intramuscular or 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.

The pharmaceutical composition of the present invention can be provided within a container, for example an ampoule, a vial or a “pen”, as described herein, to be used by the patient. For example, the pharmaceutical ition being a liquid formulation can be provided within a vial. From such vial, the t can draw up the ed dose into a syringe (in particular a single—use syringe).

The composition as described herein may be administered in a suitable amount.

The dosage of the composition of the t invention may be determined by one of the active agents of the composition to be administered, i.e. by the amount of insulin glargine or by the amount of lixisenatide. It is contemplated that in this case, the second active agent of the composition is administered in an amount defined by the fixed—dose ratio of the ition.

The dose of the composition of the t invention may be determined by the amount of natide to be administered.

In the present invention, the composition as bed herein may be stered in an amount in the range of 10 to 15 pg lixisenatide per dose or 15 to 20 pg lixisenatide per dose. in the present invention, the composition as described herein may be administered in a daily dose in the range of 10 to 20 pg lixisenatide, in the range of 10 to 15 pg lixisenatide, or in the range of 15 to 20 pg lixisenatide.

The composition as described herein may be administered by one injection per day.

The pharmaceutical composition of the present invention may be administered in a dose of 0.05 to 0.5 pg/kg body weight lixisenatide. 1717 The dose of the composition of the present invention may also be determined by the amount of insulin glargine required. :or e, the insulin glargine dose to be injected may be 40 U or less, or in a range from 10 to 40 U insulin glargine or U to 40 U insulin glargine. The insulin ne dose to be injected may also be 60 U or less, or in a range from 10 U to 60 U insulin ne or 30 U to 60 U insulin glargine. The daily insulin glargine dose to be injected may be 40 U or less, or in a range from 10 to 40 U insulin glargine or 20 U to 40 U insulin glargine. The daily insulin glargine dose to be ed also may be 60 U or less, or in a range from 10 U to 60 U n glargine or 80 U to 60 U insulin glargine.

The composition of the present invention may be administered in a dose of 0.25 to 1.5 U/kg body weight insulin glargine.

In the present invention, the composition as described herein may be a liquid ition. The skilled person knows liquid compositions of lixisenatide suitable for parenteral administration. The skilled person also knows liquid compositions of insulin glargine suitable for parenteral stration.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 — 8.8, pl- 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 - 8.5, or pH 6.0 - 8.5. The pH may be adjusted by a pharmaceutically acceptable diluted acid (typically HCl) or pharmaceutically acceptable diluted base (typically NaOH).

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 ion may comprise a tonicity agent. A suitable tonicity agent may be ed from glycerol, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium ning compounds such as CaClz.

The concentration of glycerol, lactose, sorbitol, mannitol and glucose may be in the range of 100 — 250 lel. The concentration of NaCl may be up to 150 lel. A preferred tonicity agent is glycerol. 1818 The liquid composition of the present invention may comprise methionine from 0.5 pg/mL to 20 pg/m.., preferably from 1 pg /ml to 5 pg/ml. Preferably, the liquid composition comprises L—methionine.

Yet another aspect of the present ion refers to a method of treatment of a medical indication, e or condition, as bed herein. For example, the method may comprise the administration of the ition as described herein.

The method may be a method of treatment of diabetes type 2 patients, or/and of treatment of conditions ated with diabetes type 2, as described herein. The patient may be a patient as defined herein.

A r aspect of the present invention is a method for improvement of glycemic control in diabetes type 2 ts, said method comprising stering the composition of the present invention to a patient in need thereof. in the method of the present ion, the patient may be the patient defined herein.

Yet another aspect of the present invention refers to the use of the composition as described herein for the manufacture of a composition for the treatment of a medical indication, disease or ion, as described herein. For example, the composition of the present invention can be used for the manufacture of a composition for the treatment of diabetes type 2 patients, or/and for the treatment of conditions associated with diabetes type 2. in particular, the composition of the present ion can be used for the manufacture of a composition for the improvement of glycemic control, improvement of glucose tolerance, improvement of postprandial plasma glucose concentration, improvement of postprandial plasma glucose excursion, ement of fasting plasma glucose concentration, or/and improvement of the bA1C value. The patient may be a patient as defined herein.

The invention is further illustrated by the following examples and figures.

Figure legends 1919 Figure‘t =- Kaplan—Meier cumulative incidence curve for time to treatment discontinuation due to any reason — Randomized population. lNS/LIXI = insulin GIargine/Lixisenatide =ixed Ratio ation, INS = Insulin Glargin.

Figure 2 -- Plot of mean HbAtc (%) by visit —— mITT population. LOCF = Last observation carried forward. Note: The plot included ements obtained before the introduction of rescue medication and up to 14 days after the last injection of the investigational medicinal product. X! = Insulin GIargine/Lixisenatide Fixed Ratio Combination, INS = Insulin Glargine.

Figure 3 = Plot of mean 7—point Self Monitored Plasma e (SMPG) profiles (mmol/-) at baseline and Week 24 (-OC:) ~ mITT population. _OC: = -ast observation d forward. The analysis included measurements obta'ned before the introduction of rescue medication and up to the date of last injection of the investigational medicinal product. lNS/LIXI = Insulin GIargine/Lixisenatide Iixed Ratio ation, INS = Insulin ne.

Figure 4 .. Plot of mean change in body weight (kg) from baseline by visit — mITI' population. LOCF = Last observation carried forward. The analysis included ements obtained before the introduction of rescue medication and up to 3 days after the last injection of the investigational medicinal product. INS/-IXI = n GIargine/Lixisenatide ixed Ratio Combination, INS = Insulin Glargine.

Figure 5 .. Plot of mean average daily insulin ne dose (U) by visit — mITT population. LOCF = _ast observation carried forward. The analysis included measurements obtained before the introduction of rescue medication and up to the date of last injection of the investigational medicinal product. INS/LIXI = Insulin Glargine/ ixisenatide Fixed Ratio Combination, INS = Insulin Glargine. 2020 Example 1 A randomized, 24=week, open—label, 2~arm paraiieiugroup, multicenter study comparing the y and safety of insulin giargine/iixisenatide fixed ratio combination versus insulin glargine on top of metformin in type 2 diabetic patients 1 ’ ABB'REVlATiQNS AE: ‘ Adverse event ANCOVA: Analysis of covariance BMI: Body mass index Ci: Confidence interval CMH: Cochran—Mantel—Haenszel ECG: Electrocardiogram FPG: ‘ Fasting plasma e GFR: ular filtration rate GLP—l: Glucagon—like peptide—l HLGT: High level group term HLT: High level term IMP: Investigational nal product LOCF: Last observation carried forward LS: Least squared MDRD: Modification of diet in renal e mlTT: Modified Intent—To—Treat PG: Plasma glucose PPG: Pest—prandial plasma glucose PT: Preferred term SAE: Serious adverse event SMPG: Self—monitored plasma glucose SOC‘ System organ class TEAE: Treatment-emergent adverse event 2121 2 SYNOPSIS Title of the study: A randomized, 24—week, open-label, 2»arm parallel-group, multicenter study comparing the efficacy and safety of insulin glargine/lixisenatide fixed ratio combination versus insulin glargine on top of metformin in type 2 diabetic patients Study center(s): Multicenter (67 centers) Publications (reference): NA Phase of development: Phase 2 ives: Primary obiective: To demonstrate the non-inferiority of insulin glargine/lixisenatide fixed ratio combination versus insulin glargine on glycemic control over 24 weeks, as evaluated by HbA1c reduction in type 2 diabetic patients not adequately controlled with metformin am ives: a To demonstrate the ority of insulin glargine/lixisenatide fixed ratio combination versus insulin ne on glycemic control in relation to a meal over 24 weeks, as evaluated by Z-hour Post—prandial Plasma Glucose (PPG) and glucose excursion during a standardized meal test. ’ e To assess the efficacy of insulin glargine/ lixisenatide fixed ratio ation on: - Percentage of patients reaching HbAic <7% or 566% at week 24 - 7-point Self—Monitored Plasma Glucose (SMPG) profile (each time point and mean daily value) at week 24 — Body weight at week 24 - insulin glargine dose at week 24 — Fasting Plasma Glucose (FPG) at week 24 - Percentage of patients requiring rescue y during‘the 24—week open label treatment period - 30—minute and 1—hour PPG and plasma glucose excursion during standardized meal test at week 24 — Percentage of patients reaching HbA1c <7% at week 24 with no documented symptomatic hypoglycemia during the k open label ent period - Percentage of patients reaching HbA1c <7% with no weight gain at week 24 a ",0 assess safety and tolerability of insulin glargine/ lixisenatide fixed ratio combination. a “o assess the plasma concentration of natide (in the insulin glargine/lixisenatide fixed ratio combination group) following injection on Day 1 and at Week 24. a "o assess the pment of anti-lixisenatide (for insulin glargine/lixisenatide fixed ratio ation) and antiinsulin antibodies (for both treatment groups).

Methodology: This was an openelabel, 1:1 randomized, active—controlled, 2-arm, 24~week duration, parallel-group study comparing: 2» n glargine/ lixisenatide fixed ratio (2U of insulin glargine for 1pg oflixisenatide) combination 9 insulin glargine alone The patients were stratified by screening values of HbAic (<8, 28%) and Body Mass Index (BMI) (<30, 230 kg/ m?). The study comprised 3 periods: An up—to 2-week screening period; A 24—week randomized treatment period; A 3-day safety followup period. 2222 Number of patients: Planned: 310 ized: 323 Treated: 323 Evaluated: Efficacy: 323 Safety: 323 Diagnosis and criteria for inclusion: Patients with type 2 diabetes mellitus diagnosed for at least 1 year, treated with metformin at a stable dose of at least 1.5 g/day for at least3 months prior to screening visit, and with HbAtc 27% and 310% at screening.

Study treatments lnvestigational medicinal products (llVlPs): insulin glargine/ lixisenatide fixed ratio ation and insulin glargine ation: a Tested drug: insulin glargine/ natide fixed ratio combination (100 U/mL n glarglne / 50 pg/mL lixisenatide [ratio ZU/ipgD was supplied as a sterile, aqueous solution in 3 mL cartridges to be used in a flexible dose re-usable pen (TactiPen®). a Control drug: insulin glargine was supplied as a sterile, aqueous solution in Lantus® SoloSTAR® disposable self~injector device (3mL of 100 U/mL).

Route of administration: Subcutaneous ion Dose regimen: in both groups, the initial daily dose of insulin glargine to be stered during the first week of treatment was U. Afterwards, the dose was adjusted to achieve a target fasting SMPG in the range of 80 to 100 mg/dL (4.4 to 56 ).

The dose was titrated weekly until the patient d the target fasting SMPG. Thereafter, until the end of the study, the dose was adjusted as necessary to maintain a fasting SMPG between 80 and 100 mg/dL (4.4 and 5.6 mmol/l), inclusive. Doses could be reduced or modified at any time for hypoglycemia.

In the insulin glargine/lixisenatide fixed ratio combination group, theylixisenatide dose was automatically increased or decreased ing insulin glarglne dose increase or decrease according to the 2U/i pg fixed ratio used in the combination therapy, and the maximum allowed dose of insulin glargine was 60 U (corresponding to a lixisenatide dose of 30pg). If a 60U/30pg dose was not sufficient to maintain FPG/HbAic below predefined thresholds values, the dose was to be kept at BOU and a rescue therapy was to be introduced.

Batch number 5): Not applicable to the KRM Noninvestigational nal product(s) (background therapy): metformin Formulation: Metformin 21.5 g/day.

Route of administration: Oral Dose regimen: Metformin was to be kept at stable dose throughout the study unless there was a specific safety issue related to this treatment.

Batch numberfsj: Not applicable to the KRlvl 2323 Duration of treatment: 24 weeks on of observation: Maximum duration of approximately 27 weeks.

Criteria for evaluation: Efficacy: Primam Endpoint: a Ciarge in HbAlc from baseline to Week 24 Secondary Endgoints: a Ctarge in 2—hour PPG during meal test from baseline to Week 24 a Ctarge in 2—hour plasma glucose ion during meal test from baseline to Week 24 9 Percentage of patients reaching HbAi c 36.5 % or <7 % at Week 24 e Ctarge in 7—point SMPG profiles from baseline to Week 24 (each time point and mean daily value) a Ctarge in body weight from baseline to Week 24, e Average daily Insulin glargine dose at Week 24 e Ctarge in FPG from baseline to Week 24 a Percentage of patients requiring rescue therapy during the 24—week openlabel treatment period e Ctarge in 30—minute and'l—hour PPG and plasma glucose excursion during meal test from baseline to week 24 9 tage of patients reaching HbAi c <7% at week 24 with no documented matic ycemia during the 24— week open label treatment period a Percentage of patients reaching HbAic <7% with no weight gain at week 24 Safety: Adverse events, serious adverse events, symptomatic hypoglycemia, vital signs, electrocardiogram (ECG), safety laboratory values. ' Antibody assessments: Not available in the KRM cokinetics: Not available in the KRM 2424 Statistical methods: cy: The primary efficacy population was the d intentho~Treat (mlTT) population, which included all ized patients who received at least one dose of study medication, and had both a baseline assessment and at least one postbaseline assessment of any primary or secondary efficacy variables, irrespective of ance with the study protocol and ures.

The primary endpoint (change in HbAic from baseline to week 24) was analyzed using an analysis of covariance (ANCOVA) model with treatment in glargine/lixisenatide fixed ratio combination, n glargine alone), randomization strata of screening HbAi c (<8%, 28 %), randomization strata of screening BMl (<30 kg/ m2, 230 kg/mz) and country as fixed effects and using the baseline HbAlc value as a covariate.

The ron—inferiority of insulin glargine/lixisenatide fixed ratio combination to insulin glargine alone was tested using a i—sided tical test with alpha level of 0.025 and a feriority margin of 0.4% HbAic. The feriority would be demonstrated if the upperbound of the two~sided 95% confidence interval (CI) of the difference between insulin glargine/lixisenatide fixed ratio comb‘nation and insulin glargine alone on mlTT population is 50.4%.

If non~inferiority is ished, then a corresponding check of statistical superiority of insulin glargine/ lixisenatide fixed ratio comb'nation over insulin glargine alone would be performed for the primary endpoint.

All continuous secondary efficacy endpoints were analyzed using a similar ANCOVA model with treatment, randomization strata of screeiing HbAic (<8%, 28 %), randomization strata of screening BMl (<80 kg/mz, 230 kg/mZ) and country as fixed effects and using the baseline value of the corresponding parameter as a covariate. insulin glargine dose was not included in the ANCOVA mode as a covariate since patients enrolled were n—naive.

All categorical secondary efficacy endpoints were ed by using Cochran—Mantel-Haens‘zel (CMH) method stratified by randomization strata of screening HbAic (<8%, 28 %) and BMl (<30 kg/mz, 230 kg/mZ).

Safety: The safety analysis was conducted on the safety population, defined as all randomized patients who received at least one dose of IMP (regardless of the amount of treatment administered), The evaluation of AEs, laboratory, vital sign, and ECG data was descriptive. 2525 Summary: Population characteristics: A total of 323 patients were ized to one of the two treatment groups (161 in the n glargine/lixisenatide fixed ratio ation group and 162 in the insulin glargine group). All randomized patients were d to the study ent and were included in the mle population Demographics and baseline characteristics were generally similar across the treatment groups. The median age was 58 years. The study population was primarily Caucasian (98.5%).

Efficacy results: The least d (LS) mean changes from baseline to Week 24 in HbA1c were 182% for the insulin glargine/lixisenatide fixed ratio combination group and 164% for the insulin glargine group (LS mean difference vs. ne group =. 0.17%; 95% Cl = 0.312% to 0.037%). Based on the pre-specified y is, the non-inferiority of the n glargine/lixisenatide fixed ratio combination compared to the insulin glargine on HbA1c change from baseline to week 24 was demonstrated, as the upper bound of the two—sided 95% CI of the LS mean difference was less than the predefined non—inferiority margin of 0.4%.

Statistical superiority of the insulin glargine/lixisenatide fixed ratio combination over insulin glargine was also demonstrated for this primary end points (LS mean difference vs. glargine group = 0.17%; e = 0.0130).

Treatment with insulin glargine/lixisenatide fixed ratio combination significantly improved postprandial glycemic control in comparison to insulin glargine as shown by the results for the 2—hour PPG assessment (LS mean difference of -3.17 mmol/L; p—value <.0001) and for 2~hour glucose excursion (LS mean difference of 3.24 mmol/L; p-value <.0001). in addition, patients treated with insulin glargine/lixisenatide fixed ratio combination had a statistically significant greater decrease compared to patients treated with insulin glargine in average 7»point SMPG profile (LS mean difference of 0.30 mmol/L; p—value = 0.0154).

A statistically significant difference in the body weight change from baseline to week 24 was found between the 2 treatment groups: body weight decreased in the insulin glargine/lixisenatide fixed ratio combination group and increased in the insulin ne group (LS mean body weight change from baseline to Week 24 of 0.97 kg and +0.48 kg, respectively; LS mean difference for insulin glargine/lixisenatide fixed ratio combination versus insulin ne was -1.44 kg; 95% Cl: -2.110kg, —0.773kg; p <.0001).

For average daily insulin glargine dose at Week 24 the difference between insulin glargine/lixisenatide fixed ratio combination - and insulin glargine treatment groups was borderline significant (LS mean difference of v3.24U; 95% Cl: [43.592 U to 0.114 U]; p 20.0583). Similar reduction in mean change FPG from baseline to Week 24 (L5 mean: -3.35 mmol/L in the combination group; -3.51 mmol/L in insulin glargine group) was ed. Only 1 patient (in the insulin glargine group) required rescue therapy. 2626 Safety results: nsulin glargine/lixisenatide fixed ratio combination was overall well tolerated. Slightly more patients in the insulin glargine/lixisenatideifixed ratio combination group (86 [53. 4%]) reported treatment emergent adverse events (TEAEs) than in ‘he insulin glargine group (82 [50 6%]). The most frequently reported TEAEin the combination group was nausea (12 [75%] versus 0in the insulin glargine group) :ifteen patients (9 [5.6%] for the combination group and 6 [3.7%] for the insulin glargine group) had ent emergent serious adverse events (SAEs) which were distributed over a variety of system organ classes (SOCs) without a notable 'ricrease in any specific SOC. Six (3. 7%) patients treated with the combination and none receiving insulin glargine had T:AEs eading to treatment discontinuation: for 2 of these patients, TEAEs leading to treatment discontinuation were from the gastrointestinal disorders SOC (nausea and/or ng). \lo death was ed in this study.

A total of 2 patients (1 [0.6%] in each group) reported 6 events adjudicated as allergic reactions by the Allergic Reaction Assessment Committee (ARAC). None was adjudicated as possibly related to the lMP. A total of 5 (3.1%) patients in the combination group andvi (0.6%) in the insulin glargine group) experienced ion site reactions, none of them being considered serious or severe or leading to treatment discontinuation.

No TEAE of pancreatitis or increased calcito‘nin 2 20 pg/mL was reported in the study, Forty ) patients treated with the combination had 81 symptomatic hypoglycemia events (including documented, , and probable symptomatic hypoglycemia) as compared to 40 (24.7%) patients with 84 events in the insulin glargine group. The number of events per patient-year in symptomatic hypoglycemia was MT in both treatment . No severe symptomatic hypoglycemia was reported.

Preliminary Conclusions: in these ts w'th T2DlVl uncontrolled on metformin, the feriority of the insulin glargine/lixisenatide fixed ratio combination compared to the insulin glargine on HbAic change from baseline to week 24 was demonstrated, as the upper bound of the two-sided 95% CI of the LS mean ence was less than the predefined non-inferiority margin of 0.4%.

Statistical ori y of the insulin ne/lixisenatide fixed ratio combination over insulin glargine was also demonstrated for this primary endpoint Compared to ll'lSLlll'l glargine, treatment with insulin glargine/lixisenatide fixed ratio combination led to a tically significant improvement in postprandial glycemic control (as shown by the results for 2~hour PPG and glucose excursion after a standard liquid breakfast meat) and in the e of the 7-point SMPG e. Furthermore the combination had a tically better effect on body weight compared to insulin glargine Overall, the insulin glargine/lixisenatide fixed ratio combination was well tolerated. The safety profile in the combination group was lly cons‘stent with the known safety profile of the GLP-1 receptor agonist class without major ences compared to the insulin glargine group. Nausea was the most frequently reponed adverse event in the combination group. The incidence . ~ of symptomatic hypoglycemia. (including nted, severe, and probable symptomatic hypoglycemia) was'similar in both treatment groups. in conclusion, the insulin glargine/lixisenatide fixed ratio combination added to metformin for patients not well controlled with this treatment, significantly improved HbA‘lc and reduced PPG and body weight in comparison to the insulin glargine. The safety profile was consistent with the known effects of GLP—i receptor agonists, the main AE being nausea. 2727 3‘ RESULTS 3.1 STU )Y PATIENTS 3.1.1 Patient accountab.'lity Of the 520 patients screened, 323 (62.1%) patients were randomized to one of the two treatment groups (161 in the combination group, 162 in the insulin glargine group) in 67 centers distributed among 13 countries (Chile Czech Republic Germany, Denmark France Hungary, Lithuania Mexico Poland Romania Slovakia Sweden, and United States ofArnerica). The main reason fer screening failure was HbAlc value at screening visit out of the ol defined range (133 [25.6%] out of 520 screened patients). All 323 randomized patients were d to open— label treatment and included in the mlTT population for efficacy es (Table 1).

Table 1 — Analysis populations Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine All Randomized population 161 (100%) 162 (100%) 323 (100%) Efficacy population Modified Intent-to—Treat (mlTT) 161 (100%) 162 (100%) 323 (100%) Safety population 161 162 323 Note: The safety population patients are tabulated according to treatment actually received (as treated).

For the other populations patients are tabulated according to their ized treatment.

Thereis no t randomizedin a group and taking another study treatment ............ n “"" ' 3.1.2 Study. disposition Table 2 provides the summary of patient disposition for each ent group.

During the 24—week study treatment , 11 (6.8%) combination—treated patients prematurely tinued the IMP, compared with 3 (1.9%) insulin glargine—treated patients. For combination— treated patients, the most common reasons for treatment discontinuation was “adverse event” (6 patients [3.7%] versus 0 t in the insulin glargine group) followed by “other reasons” (4 patients [2.5%] versus 2 patients [1.2%] in the insulin glargine group).

The o—treatment discontinuation due to any reason is depicted in Figure 1. 2828 Table 2 — Patient ition — ized population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine (N=161) (N=162) Randomized and treated - 161 (100%) 162 (100%) Complete the study treatment period 150 (93.2%) 159 (981%) Did not complete the study treatment period 11 (6.8%) 3 (1.9%) Subj ect's decision for treatment discontinuation 10 (6.2%) 3 (1.9%) Reason for treatment discontinuation Adverse event 6 0 p (3.7%) Lack of y 0 0 Poor compliance to protocol 1 (0.6%) 1 (0.6%) Lost to follow—up 0 O Other reasons 4 (2.5%) 2 (1.2%) Figure 1 ~ —Meier cumulative incidence curve for time to treatment discontinuation due to any reason ~ Randomized population " Symb01=Censor -: «2 INS g 10- its ————————— ______1was»:- a ______ E ______ . __ .‘E ..... g —a~m ———————————— a QAI““I“‘I"‘I T't““1""T""I“r‘l 0 30 6O 90 120 150 180 210 240 Number at Risk )ays Since First Open Label IMP INS/LIXI' 161 159 157 153 151 150 1 'O INS 162 160 160 160 ‘ 160 160 1 1 OO 2929 INS/Lle = Insulin Glargine/Lixisenatide Fixed Ratio Combination, INS = Insulin Glargine. ,3-13 )emographics and baseline characteristics Table 3 es the summary of demographics and patient characteristics at screening or baseline.

The demographic and patient characteristics were generally r between the two treatment groups for the ized population. The median age was 58 years. The study population was ily Caucasian (98.5%).

Table 3 - Demographics and patient characteristics at ing or baseline — Randomized population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine All (N=161) (N=162) (N=323) Age (years) Number 161 162 323 Mean (SD) 56.9 (9.5) 56.6 (9.4) 56.7 (9.4) Median 58.0 57.0 58.0 Min : Max 24: 80 30 :78 24:80 Age group (yeaIS) [11 (%)1 Number 161 162 323 < 50 31 (19.3%) 39 (24.1%) 70 (21.7%) 2 50 to < 65 98 ) 91 (56.2%) 189 (58.5%) 265to<75 31 (19.3%) 30 (18.5%) 61 (18.9%) 2 75 1 (0.6%) 2 (1.2%) 3 (0.9%) Gender [n (%)] Number 161 162 323 Male 80 (49.7%) 85 (52.5%) 165 (51.1%) Penile 81 (50.3%) 77 (47.5%) 158 (48.9%) Race [n (%)] Number ' 161 162 323 Caucasian/White 158 (98.1%) 160 (98.8%) 318 (98.5%) Black 2 (1.2%). 1 (0.6%) 3- (0.9%) Asian/Oriental 1 (0.6%) 1 (0.6%) 2 (0.6%) Other 0 0 0 303O Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine All (N=161) (N=162) =323) Ethnicity [n (%)] Number 161 162 323 Hispanic 35 (21.7%) 30 (18.5%) 65 (20.1%) Non Hispanic 126 (78.3%) 132 (81.5%) 258 (79.9%) Screening lszlc (%) Number 161 162 323 Mean (SD) 8.12 (0.80) 8.08 (0.77) 8.10 (0.78) Median 7.90 7.90 7.90 Min : Max 7.0 : 10.0 7.0 : 9.8 7.0 : 10.0 Randomization strata of Screening HbAlc(%) [n(%)] Number 161 162 323 <8% 81 ) 82 (50.6%) 163 (50.5%) 2 8% 80 (49.7%) 80 (49.4%) 160 (49.5%) Screening BMI (kg/m2) Number 161 162 323 Mean (SD) 32.30 (4.78) 32.08 (4.27) 32.19 (4.53) Median 32.45 31.92 32.10 Min : Max 20.5 :399 23.2 : 40.0 20.5 : 40.0 Randomization strata of Screening BMI (kg/m2) [n (%)1 Number .161 162 323 < 3 0 51 (31.7%) 51 (31.5%) 102 (31.6%) Z 3 0 110(68.3%) 111 (68.5%) 221 (68.4%)- ne BMI (kg/m2) Number 161 162 323 Mean (SD) 32.24 (4.75) 32.02 (4.35) 32.13 (4.55) Median 32.53 31.53 32.08 Min : Max 21.0 : 40.3 23.1 :411 21.0 :41.1 Baseline BMl categories ) [nv(%)] Number 161 162 323 < 30 51 (31.7%) 51 (31.5%) - 102 (31.6%) 2 30 110 ) 111 (68.5%) 221 (68.4%) BM1= Body Mass Index. 3131 The ic history and e characteristics were generally comparable between the ent groups, as shown in Table 4. The on of use and the average daily dose of metformin were similar between the two treatment groups; at baseline, the mean dose was 2084.75 mg for the randomized population. Efficacy Variables at baseline were similar across the two ent groups and are shown in Section 3.2 CY.

Table 4 — Disease characteristics at screening or baseline — Randomized population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine All (N=161) (N=162) (N=323) Duration of diabetes (years) Number 161 162 323 Mean (SD) 6.29 (4.29) 7.10 (5.27) 6.69 (4.82) ’ Median 5.42 5.35 5.35 Min : Max 1.0 :22.4 1.0 : 23.3 1.0 : 23.3 Age at onset of Type 2 diabetes ) .

Number 161 162 323 Mean (SD) 50.6 (9.6) 49.4 (9.3) 50.0 (9.4) Median 52.0 50.0 51.0 Min: Max 20 : 77 25 :74 20 :77 . History of gestational diabetes [n (%)] Number (Female) 81 77 15 8 Yes (Female) 9 (11.1%) 4 (5.2%) 13 (8.2%) No (Female) 72 (88.9%) 73 (94.8%) 145 (91.8%) Duration of metfon’nin treatment (years) Number 161 162 323 Mean (SD) 4.10 (3.63) 4.31 (3.93) 4.21 (3.78) Median 3.27 3.08 - 316' Min : Max 0.3 :20.3 0.3 : 22.1 0.3 :22.1‘ Daily dose ofmetformin at baseline (mg) Number ’ 161 162 323 Mean (SD) 2075.78 (440.71) 2093.67 (415.51) 2084.75 (427.68) Median 2000.00 2000.00 2000.00 _Min : Max 1500.0 : 3000.0 1500.0 : 3000.0 1500.0 : 3000.0 3232 Insulin Glgrgine/Lixisenatide Fixed Ratio Combination Insulin Glargine All (N=161) (N=162) (N=323) Categorized dai1y dose of metformin at baseline (mg) [n (%)] Number 161 162 323 <1500 0 0 O < 2500 112 (69.6%) 117 (72.2%) 229 (70.9%) 2 2500—< 3000 37 ) 32 (19.8%) 69 (21.4%) _>. 3000 12 (7.5%) 13 (8.0%) 25 (7.7%) Prior use of GLP—1 receptor agonist [n (%)1 Number 161 162 323 Yes 5 (3.1%) 8 (4.9%) 13 (4.0%) No 156 (96.9%). 154 (95.1%) 310 (96.0%) Prior use of insulin [n (%)] Number 161 162 323 Yes 2 (1.2%) 9 (5.6%) 11 (3.4%) No 159 (98.8%) 153 (94.4%) 312 (96.6%) Diabetic retinopatby [n (%)] Number 161 162 323 Yes 3 (1.9%) 7 (4.3%) 10 (3.1%) No 153 (95.0%) 149 ) 302 (93.5%) Unknown 5 (3.1%) 6 (3.7%) 11 (3.4%) Diabetic sensory or motor neuropathy [n (%)1 Number 161 162 - 323 Yes 26 (16.1%) 25 (15.4%) 51 (15.8%) No 127 (78.9%) 133 (82.1%) 260 (80.5%) n 3 (50%) 4 (2.5%) 12 (3.7%) Diabetic autonomic neuropathy [n (%)] Number 161 162 323 Yes 1 (0.6%) 2 (1.2%) 3 (0.9%) No 146 (90.7%) 151 ) 297 (92.0%) Unknown 14 (8.7%) 9 (5.6%) 23 (7.1%) 3333 Insulin Glargine/Lixisenatide Fixed Ratio Combination - Insulin Glargine All (N=161) (N=162) ) Diabetic nepbropathy [n (%)] Number 161 162 323 Yes 8 (5.0%) 8 (4.9%) 16 (5.0%) No 141 (87.6%) 148 (91.4%) 289 (89.5%) Unknown 12 (7.5%) 6 (3.7%) 18 (5.6%) GLP—1 = Glucagon like peptide-1. _ 3.1.4 Dosage and duration Treatment exposure and final insulin dose are summarized in Tables 5 and 6. The median duration of treatment exposure was 1690 days in each treatment group.

Table 5 - Exposure to investigational product — Safety population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine (N=161) (N=162) Cumulative exposure to treatment (patient years) 71.8 74.3 Duration of study treatment (days) Number ' 161 162 Mean (SD) . 162.9 (27.5) 167.5 (18.2) Median 169.0 169.0 Min:Max 1:181 2:219 Duration of study treatment by category [11 (%)] . g duration ’0 0 1-14 days 2 (1.2%) 1 (0.6%) 1528 days 0 1 (0.6%) 29~56 days 1 (0.6%) 0 57—84 days 3 (1.9%) 0 85—168 days 31 ) 42 (25.9%) >168 days . 124 ) 118 (72.8%) 3434 Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine ) (N=l62) Missing duration - 0 0 21 day 161 (100%) 162 (100%) 215 days 159 (98.8%) 161 ) 229 days 159 (98.8%) 160 (98.8%) 257 days 158 160 p (98.1%) (98.8%) 2 85 days 155 (96.3%) 160 (98.8%) 2169 days 124 (77.0%) 118 (72.8%) Note: Patients are considered in the treatment group they actually received at randomization Duration of exposure = (date of the last open-label 1MP injection —date of the first open—label 1MP injection) + 1.

In the combination group the final daily dose at the end of the treatment period was >20U/10ug and 0ug for 70 ) patients and >40U/20ug and S6OU/30ug for 68 (42.2%) patients.

More patients (23[14.3%]) in the combination group than in the insulin glargine group (16 [9.9%]) had a final daily dose in the ry of SZOU. More patients in the insulin glargine group (27 [16.7%]) had a final daily dose >60 U compared to the combination group (0 t as required by the protocol).

Table 6 — Number (%) of patients by final insulin doSe at the end of the abel treatment — Safety population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargin‘e Final Insulin dose (N=161) (N=162) £20 U . 23 (14.3%) 16 (9.9%) >20 U to £40 U 70 (43.5%) 73 (45.1%) >40 U to £60 U 68 (42.2%) 46 (28.4%) >60 U . 0 27 ) Note: Percentages are calculated using the number of safety patients as the denominator. 3.2 «inanACY 3.2.1 Primary efficacy endpoint Main analysis Table 7 summarizes the results of the primary efficacyendpoint, change from baseline to Week 24 in HbAl c using an ANCOVA analysis with missing data imputed using the last observation 3535 d forward (LOCF) approach. The least squared (LS) mean changes from baseline to Week 24 in HbAlc were —1.82% for the combination group and ~1.64% for the insulin glargine group (LS mean difference vs insulin glargine = 017%, 95% CI: —0.3 12% to 0.037%). Based on the pre—specifred primary analysis, the non—inferiority of the combination group compared to the insulin glargine group was trated, as the upper bound of the two—sided-95% C1 of the LS mean difference was less than the predefined non-inferiority margin of 0.4%. Statistical superiority of the combination over insulin glargine was also demonstrated (LS mean difference vs. insulin ne = —0.17%, p—Value = 0.0130).

Figure 2 illustrates the Mean (2813) in HbAlc over time during the 24—week treatment period. In both treatment groups; the largest decrease in HbAlc mean was observed at Week 24.

Table 7 — Mean change in HbAlc (%) from baseline to Week 24 ~ mITT population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine HbAlc (%) (N=161) (N=162) Number 160 161 Mean (SD) 8.06 (0.79) 8.01 (0.81) Median 7.90 7.80 Min : Max, 6.3 :102 6.7: 10.0 Week 24 (LOCF) Number 160 161 Mean (SD) 6.31 (0.72) 6.47 (0.64)‘ Median 6.15 6.40 MinzMax 5119.1 5.1187 Change from baseline to Week 24 (LOCF) Number ' 160 161 Mean (SD) —1.76 (0.84) 154 (0.87) Median —1.60 —1.40 Min : Max —4.3 : 0.4 —3.7 : 0.9 LS Mean (SE) a 0.058) -1.64(0.057) LS Mean difference (SE) vs. insulin glargine a —0.17 (0.070) 95% C1 (0.312 to 0037) 3636 Insulin Glargine/Lixisenatid'e Fixed Ratio Combination n Glargine HbAlc (%) ‘ (NT—“161) (N=162) p-value 0.0130 LOCF = Last observation carried forward. , 3 Analysis of covariance (ANCOVA) model with treatment groups (insulin glargine/lixisenatide fixed dose combination, insulin glargine), randomization strata of ing HbAlc (<8r0%, 28.0%), randomization strata of ing 3M1 (<30, 230 kg/mz), and country as fixed effects and baseline HbAl c value as a ate.

The analysis included ements obtained before the introduction of rescue medication and up to 14 days after the last injection of the investigational medicinal product.

Patients w'th both ne and Week 24 (LOCF) measurements are included Figure 2 — Plot of mean HbAlc (%) by visit ~ mITT population 9.0 ~ 85 ~ 24LoCF LOCF = Last observation carried forward.

Note: The plot included measurements obtained before the introduction of rescue medication and up to 14 days after the last injection of the investigational medicinal product.

INS/LIXI = Insulin Glargine/Lixisenatide Fixed Ratio Combination, INS = n Glargine.

Table 8 provides the proportion of responders with HbAlc £6.5% 0r <7% at Week 24, respectively; Although the between—group differences were not statistically significant as shown by the 95% CI of proportion difference, a higher percentage of patients in the ation group reached target HbAlc 36.5% (71.9% versus 64.6%) or <7 % (84.4% versus 78.3 %) as compared with the insulin glargine group. ' 3737 Table 8 — Number (%) of patients with HbAlc value 56.5% or <7% respectively at Week 24 « mITT population .

Insulin GIargine/Lixisenatide Fixed Ratio Combination Insulin Glargine HbA1c(%) (N=161) (N=162) Number 160 161 36.5% 115 ) 104 ) Proportion ence (95% Cl) vs. insulin glarginefl 7.3% (263% to 17.28%) — Number 160 161 <7.0% 135 (84.4%) 126 (78.3%) tion difference (95% CI) vs. insulin nea 6.2% (216% to 14.47%) - ‘Weighted average of proportion difference between treatment groups (insulin glargine/lixisenatide fixed dose combination, insulin glargine) from each strata (randomization strata of screening HbAlc [<8.0, 28.0%], randomization strata of screening BMI [<30 or 230 kg/mZD using Cochran—Mantel—Haenszel (CMH) weights.

Proportion difference = difference of the proportions of patients achieving HbAl‘c value 56.5% or <7% respectively. _ The analysis included measurements obtained before the introduction of rescue medication and up to 14 days after the last injection of the igational medicinal product. 3.2.2 Other key efficacy endpoints Table 9 to Table 14 summarize the ANCOVA analyses of 2—hour PPG, PG excursion, average 7— point SMPG profile, body weight, average insulin daily dose, and FPG, respectively. Figures 3 to illustrate average 7—point SMPG profile, body , and average insulin daily dose over time during the treatment period.

Treatment with the combination significantly improved postprandial glycemic control in comparison to insulin ne as shown by the results for the 2—hour PPG and PG excursion. For 2—hour PPG (Table 9), the LS mean change from baseline to Week 24 was ~7.49 Inrnol/L for the combination group and — 4.33 mmth for the insulin glargine group (LS mean difference vs insulin glargine = —3.17 mmol/L; e <.0001). For 2—hour PG excursion (Table 10), the LS mean change from baseline to Week 24 was —3.91 1111110le for the combination group and —Oi67 mmol/L for the insulin glargine group (LS mean difference versus insulin glargine = ~3.24 ; e <.0001). 3838 Table 9 ~ Mean change in 2—hour postprandial plasma glucose (mmol/L) from baseline to Week 24 — mlTT population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine 2-hour postprandial plasma glucose (mmol/L) ) (N=162) Baseline Number 151 153 Mean (SD) 16.08 (3.62) 15.51 (3.88) Median 15.90 1540 Min : Max 7.8 : 26.6 5.6 : 24.8 Week 24 (LOCF) Number 151 153 Mean (SD) 8.51 (3.23) 11.55 (2.83) Median 7.80 11.10 Min: Max 3.4: 19.7 3.5 220.3 Change from baseline to Week 24 (LOCF) Number 151 153 Mean (SD) —7.56 (4.34) 396 (4.05) Median -7.50 —3.90 Min : Max —18.2 : 5.1 —14.9 : 14.1 is Mean (SE) a 4.49 ) 41.33 (0.274) LS’Mean ence (SE) vs. insulin glargine a —3.17 (0.337) 95% Cl (—3.832 to —2.504) p—Value '<.0001 LOCF = Last observation canied forward. 3 Analysis of covariance (ANCOVA) model with treatment groups (insulin glargine/lixisenatide fixed dose combination, insulin glargine), randomization strata of screening HbAlc , 28.0%), randomization strata of ing BMI (<30, :30 kg/mz), and country as fixed effects and baseline 2—hour postprandial plasma glucose value as a ate.

The analysis included measurements obtained before the introduction of rescue medication and up to the date of the last1nj ection of the 1nvest1gational medicinal product Patients with both baseline and Week 24 (LOCF) measurements are included. 3939 Table 10 — Mean change in 2-hour plasma glucose excursion (mmol/L) from baseline to Week 24 ~ mlTT ‘ population Insulin ne/Lixisenatide Fixed Ratio Combination Insulin Glargine 2—hour plasma glucose excursion (mmol/L) (N=161) (N=162) Baseline ‘ ' Number 151 152 Mean (SD) 6.04 (2.67) . 5.94 (2.95) Median ‘ 5.90 5.80 Min : Max ~31 : 13.6 -4.3 2133 Week 24 (LOCF) Number 151 152 Mean (SD) 2.15 (3.18) 5.33 (2.79) Median 1.90 5.05 x 71:12.8 - 1.1 Change from baseline to Week 24 (LOCF) Number 151 152 Mean (SD) 389 (3.75) 061 (3.03) Median -3.70 ' —0.75 Min : Max —13.2 : 7.5 —7.6 : 13.7 LS Mean (SE) a —3.91 (0.277) —0.67 (0.269) LS Mean ence (SE) vs. insulin glargine a ~ —3.24 (0.331) 95% C1 (3895 to 2592) p-value <~0001 LOCF = Last observation carried forward. 3 Analysis of covariance (ANCOVA) model with treatment groups (insulin glargine/lixisenatide fixed dose combination, insulin glargine), randomization strata of screening HbAlc (<8.0%, 28.0%), randomization strata of screening BMI (<30, Z30 , and country as fixed s and baseline 2—hour plasma glucose excursion value as a covariate.

The analysis included measurements obtained before the introduction of rescue medication and up to the date of the last ion of the investigational medicinal product. ts with both baseline and Week 24 (LOCF) measurements are included.

For the average 7—point SMPG (Table 11), the combination—treated patients had‘a statistically significant greater reduction compared to the insulin glargine—treated patients (LS mean difference of —O.30 mmol/L; p—value = 0.0154). Figure 3 illustrates the 7—point SMPG for each timepoint at baseline and week 24 (LOCF). 4040 Table 11 — Mean change in average t Self Monitored Plasma Glucose (SMPG) profiles (mmol/L) from baseline to Week 24 ~ mITT population Insulin Glargine/Lixisenatide Fixed Ratio ation Insulin Glargine Average 7—point Self Monitored Plasma Glucose (SMPG) (mmol/L) (N=161) (N=162) Baseline Number 149 155 ' Mean (SD) 10.01 (2.49) 9.82 (2.10) Median 9.56 9.47 Min : Max 6.0 : 24.2 5.7 : 17.3 Week 24 (LOCF) Number 149 155 Mean (SD) 6.74 (1.12) 7.01 (1.15) Median 6.57 6.94 Min: Max - 47:11.4 4.8 ; 10.6 Change from baseline to Week 24 (LOCF) Number 149 155 Mean (SD) —3.27 (2.59) -2.81 (2.18) Median —2.80 —2.31 Min : Max -174 : 2.3 —12.0 : 0.8 LS Mean (SE) a 3.23 (0.104) —2.93 (0.101) LS Mean difference (SE) vs. insulin glargine a —0.30 (0.125) 95% CI 0 to —0.058) p-Va1ue 0.0154 LOCF = Last observation carried d. 8 Analysis of covariance (ANCOVA) model with treatment groups (insulin ne/lixisenatide fixed dose combination, n glargine), randomization strata of screening HbAlc (<8.0%, 28.0%), randomization strata of screening BMI (<30, 230 kg/m2), and country as fixed effects and baseline average 7—point SMPG value as a covariate.

The analysis included measurements obtained before the introduction of rescue medication and up to the date of the last injection of the investigational medicinal product. 4 Patients With both baseline and Week 24 (LOCF) measurements are included. 4141 Figure 3 — Plot of mean 7—point Self Monitored Plasma Glucose (SMPG) profiles (mmol/L) at baseline and Week 24 (LOCF) — InITT population (mmol/L) Mean 7‘0 ‘ . _ III @ 6.5 - 6.0 / '5 A F I. l T I l l l Pie—breakfast ggstt- Preluneh 8193’s Predmner 241W» Bedlam: a~e~~e INS/[DUABaseline n=l59) 6+9 INS—Baseline F150) 0—0-0 lNS/LlXLWeek24 OCF (n=lSl) E—Z—E lNSWeek24 (F153) LOCF = Last observation cariedforward. "he analysis included measurements obtained before the introduction ofrescue medication and up to the date of last i'lj ection of the investigational medicinal product.

XI = Insulin Glargine/nixisenatide Fixed Ratio Combination, INS = Insulin Glargine. 4242 The LS mean body weight decreased from baseline to week 24 by 0.97 kg for the combination— treated patients and increased by 0.48 kg for the insulin glarginetreated patients (LS mean ence versus insulin glargine— —l.44 kg) with statistically cant difference observed between treatment groups (p—Value <0.001) (Table 12) Table 12 - Mean change in body weight (kg) from baseline to Week 24— mITT tion Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin ne Body weight (kg) (N=161) ) Baseline Number 159 160 Mean (SD) 90.26 (17.63) 91.70 (16.62) Median 90.60 91.20 Min : Max 45.7: 138.0 54.2 : 173.6 Week 24 (LOCF) Number 159 160 Mean (SD) 89.10 (16.89) 92.09 (16.30) Median 90.60 91.00 ' Min : Max‘ 44.1 : 129.0 56.3 .: 1734 Change from baseline to Week 24' (LOCF) Number 159 160 Mean (SD) —1.16 (3.45) 0.39 (2.96) Median -1.00 0.35 > Min : Max 0 :7.2 ~10.0 : 8.2 LS Mean (SE) a —0.97 (0.289) 0.48 (0.282) LS Mean difference (SE) vs. insulin glargine a ~1.44 (0.340) 95% Cl ’ ' (—2.1 10 to -0.773) p—Value <.OOOl LOCF= Last observation carried forward.

Analysis of covariance (ANCOVA) model with treatment groups (insulin glargine/lixisenatide fixed dose combination, insulin glargine), randomization strata of screening HbAlc , 28.0%), randomization strata of screening BMl (<30 >30 kg/mz) and country as fixed effects and baseline body weight as a covariate The is included measurements obtained before the introduction of rescue medication and up to 3 days after the lastinj ection of the investigational medicinal product.

Patients with both baseline and Week 24 (LOCF) measurements are included. 4343 Figure 4 — mITT population — Plot of mean change‘in body weight (kg) from ne by Visit 2 -1 GOJD -_ :; 0‘ 2 l .2 - l I l | T ' I I 8 12 16‘ 20 24 24LOCF Week LOCF = Last observation canied forward“ The analysis included measurements obtained before the introduction of rescue medication and up to 3 days after the last injection of the investigational medicinal product INS/LIXI = Insulin Glargine/Lixisenatide Fixed Ratio Combination, INS =lnsu1in Glargine. '\__, 4444 The LS mean in average insulin glargine daily dose at Week 24 was 36.08 U_ for the combination group and 3932 U for the insulin glargine group, and the ence between the treatment groups was borderline significant (LS mean difference vs insulin glargine = —3.24 U; p—value = 0.0583) (Table 13). ‘ Table 13 - Average daily insulin glargine dose (U) at Week 24 — mITT population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Average daily insulin glargine dose (U) (N=161)’ . (N=162) Week 24 (LOCF) Number 161 . 162 Mean (SD) 37.90 ) 41.54 (1837) Median 38.00 ' 38.00 Min 2 Max 10.0 : 64.0 10.0 : 98.6 LS Mean (SE) a 36.08 (1.415) 39.32 (1.384) LS Mean difference (SE) vs. n glargine a —3.24 ) 95% c1 (—6.592 to 0.114) p—value 0.0583 LOCF = Last observation carried forward. a Analysis of variance (ANOVA) model with treatment groups (insulin ne/lixisenatide fixed dose combination, insulin glargine), randomization strata of screening HbAlc (<8.0%, 28.0%), randomization strata of screening 3M1 (<3 0, 230 , and country as fixed effects.

The analysis included measurements ed before the introduction of rescue medication and up to the date of last injection of the investigational medicinal product. ‘ 4545 Figure 5 — Plot of mean average daily insulin glargine dose (U) by Visit — mITT population Mean LOCF.= Last observation carried d.

The analysis included measurements obtained before the introduction of rescue medication and up to the date of last injection of the investigational medicinal product.

INS/LEG = Insulin Glargine/Lixisenatide Fixed Ratio ation, INS = Insulin Glargine. 4646 Similar reduction in mean change FPG from baseline to Week 24 (LS mean: ~3.35 mmol/L in the combination group; —3.51 mmol/L in insulin glargine group) was observed.

Only one t in the insulin glargine group required rescue y during the 24 weeks treatment period. ’ Table 14 — Mean change in fasting plasma glucose (mmol/L) from baseline to Week 24 ~ mITT population Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin ne Fasting plasma glucose (mmol/L) (N=161) (N=162) Number ' 159 160 Mean (SD) 9.79 (2.19) 9.48 (2.16) Median 9.40 9.10 Min: Max 6.2 : 23.0 3.8: 18.4 Week 24 (LOCF) Number 159 160 Mean (SD) 6.39 (1.58) 6.20 (1.35) Median 6.20 595 Min ; Max 4.2 : 15.1 3.1 : 10.9 Change from baseline to Week 24 (LOCF) Number 159 160 Mean (SD) 3.40 (2.09) 6.28 (2.39) Median —3.30 ‘ 300 Min : Max —14.9 :2.8 -13.6 24.4 LS Mean (SE) a —3.35 (0.130) —3.51 ) LS Mean difference (SB) vs. insulin glargine a 0.16 (0.156), 95% CI (—0.143 to 0.471) p—value . 0.2940 . LOCF‘= Last observation carried forward. 3 Analysis of covariance (ANCOVA) model with treatment groups (insulin glargine/lixisenatide fixed dose combination, insulin glargine), randomization strata of screening HbAl c (<8.’0%-, 28.0%), randomization strata of screening BMI (<3 0, 230‘kg/m2), and country as fixed effects and baseline fasting plasma glucose as a covariate.

The analysis included measurements obtained before the introduction of rescue medication and up to 1 day after the last injection of the investigational medicinal product.

Patients with both ne and Week‘24 (LOCF) ements are included. 4747 3.3 SAFETY Symptomatic ycemia events were documented on a c hypoglycemia event form, and not an AB CRF page, and thus were not ed in the TEAE ies. They are summarized separately from TEAES (see Section 3.3.5). 3.3.1 Treatment—emergent adverse events Table 15 presents the overall summary of patients who had adverse events during the k open—label treatment period. Slightly more patients ed TEAES in the combination group (86 ]) than in the n glargine group (82 [50.6%]), which is mainly attributable to the difference in gastrointestinal disorders SOC events (25 [15.5%] in the combination group vs [9.3%] in the insulin glargine group). As shown in Table 16, the most frequently reported TEAE in the combination group was nausea (12 [7.5%] versus 0 in the insulin glargine , and in the insulin glargine group was headache (12 [7.4%] versus 8 [5.0%] in the combination group).

Table 15 — Safety population - Overview of adverse event profile: treatment emergent adverse events Insulin Glargine/Lixisenatide Fixed Ratio Insulin Combination Glargine (N=1 6 1) (N=162) Patients with any TEAS 86 (53.4%) 82 ) Patients with any t‘eatment emergent SAE 9 (5.6%) 6 (3.7%) Patients with any 0 0 - EA: leading to death Patients with any a leading to permanent treatment discontinuation 6 i .1 (3.7%) O TEAE: Treatment energent adverse event, SAE: Serious adverse event. n (%) = number and oercentage of patients with at least one TEAS.

Table 16 — Number (%) of patients with TEAE(S) that occurred With PT >=1% in any treatment group by primary SOC, HLGT, HLT and PT »— Safety population Insulin i PJMARY SYSTEM ORGAN CLASS ne/Lixisenatide HLGT: High Level Group Term . Fixed Ratio Insulin HLT: High Level Term Combination ' Glargine Preferred Term n(%) (N=161) . (N=162) Any TEAE’ 86 (53.4%) . 82 (50.6%) Infections and infestations 33 (20.5%) 38 (23.5%) HLGT: Infections — pathogen unspecified .. 27 (16.8%) 31 (19.1%) HLT: Abdominal and gastrointestinalinfections 5 (3.1%) 1 (0.6%) Gastroenteritis 5 (3.1%) 1 (0.6%) 4848 Insulin PRIMARY SYSTEM ORGAN CLASS Glargine/Lixisenatide HLGT: High Level Group Term Fixed Ratio Insulin HLT: High Level Term Combination Glargine red Term n(%) (N=161) (N=162) I-ILT; Dental and oral soft tissue infections 0 3 (1.9%) Tooth s O 2 (1.2%) “LT: Lower respiratory tract and lung infections 3 (1 .9%) 1 (0.6%) Bronchitis 3 (1.9%) 1 (0.6%) FLT: Upper respiratory tract infections 15 (9.3%) 21 (13.0%) Nasopharyngitis 9 (5.6%) 9 (5.6%) Rhinitis 2 (1.2%) 2 (1.2%) Sinusitis O 3 (1.9%) Upper respiratory tract infection 3 (1.9%) 5 (3.1%) HLT: Urinary tract infections 4 (2.5%) 3 (1.9%) Cystitis 2 (1.2%) 2 (1.2%) Urinarytract infection 2 (1.2%) _1 (0.6%) HLGT: Viral infectious disorders 6 (3.7%) 8 (4.9%) HLT: Influenza Viral infections 4 (2.5%) 6 (3.7%) Influenza 4 (2.5%) 6 (3.7%) Metabolism and nutrition disorders 6 (3.7%) 1 (0.6%) HLGT: Appetite and general nutritional ers 2 (1.2%) l p (0.6%) HLT: Appetite disorders 2 (1.2%) l (0.6%) Decreased appetite 2 O . (1.2%) HLGT: Lipid metabolism disorders 4 (2.5%) 0 HLT: Elevated triglycerides 2 (1.2%) O Hypertiiglyceiidaemia 2 (1.2%) 0 Psychiatric disorders 6 (3.7%) 2 (1.2%) HLGT: Depressed mood ers and disturbances 0 2 (1 .2%) HLT: Depressive disorders 0 2 (10.2%) sion 0 2 (1.2%) HLGT: Sleep disorders'and disturbances 4 (2.5%) 0 HLT: bances in initiating and ining sleep 3 (1.9%) 0 Insomnia 3 (1.9%) O Nervous system disorders ' 19 (11.8%) 20 (12.3%) HLGT: Headaches 9 (5.6%) 13 (8.0%) HLT: Headaches NBC 8 (50%) 1‘2 (7.——%) Headache 8 (5.0%) 12 (7.4%) HLGT: heurological disorders NBC 7 (4.3%) 5 (3.1%) HLT: Neurological signs and symptoms NBC 3 (1.9%) 3 (1.9%) Dizziness 3 (1.9%) 1 (0.6%) 4949 PRIMARY sysr dM ORGAN CLASS Glarginlgiggenafide HLGT: ligh Level Group Term Fixed Ratio Insulin » HL : High Level Term Combination Glargine Preferred Term n(%) (N=161) (N=162)' Presyncope 0 2 (1.2%) HLGT: Peripheral neuropathies 2 (1.2%) 2 (1.2%) HLT: Chronic polyneuropathies 2 (1.2%) 2 (1.2%) Diabetic neuropathy 2 (1.2%) 2 (1.2%) HLGT: Spinal cord and nerve root disorders 2 (1.2%) 2 (1.2%) HLTIALurnbar spinal cord and nerve root disorders 2 (1.2%) 2 (1 .2%) Sciatica 2 (1.2%) 2 (1.2%) Eye disorders 4 (2.5%) 7 - (4.3%) HLGT: Ocular infections, tions and inflammations 3 (1.9%) 4 (2.5%) HLT: Conjunctival infections, irritations and inflarrnnations 3 (1.9%) 2 (1.2%) Conjunctivitis 2 (1.2%) 2 (1.2%) Bar and labyrinth disorders 0 2 . (1.2%) HLGT: Inner ear and Vlllth cranial nerve disorders 0 2 (1.2%) HLT: Inner ear signs andsyrnptoms 0 2 (1.2%) Tinnitus o 2 (1.2%) c ers 4 (2.5%) 1 (0.6%) HLGT: c arrhythmias 2 (1.2%) l (0.6%) HLT: Supraventn‘cular arrhythmias 2 (1.2%) 1 (0.6%) Atria1 ation 2 (1.2%) 1 (0.6%) Vascular disorders 3 (1.9%) 3 (1.9%) HLGT: Vascular hypertensive disorders 1 (0.6%) 2 (1.2%) HLT: Vascular hypertensive disorders NBC 1 (0.6%) 2 (1.2%) Hypertension 1 (0.6%) 2 (1.2%) ’ Respiratory, thoracic and mediastinal disorders 6 (3.7%) 4 (2.5%) HLGT: Respiratory ers NBC 3 (1.9%) 2 (1.2%) HLT: Coughing and associated symptoms 2 (1.2%) O Cough 2 (1.2%) O Gastrointestinal disorders 25 (15.5%) 15 (9.3%) HLGT: Gastrointestinal motility and defaecation conditions 8 (5.0%) 7 (4.3%) HLT: Diarrhoea (excl infective) 5 (3.1%) 6 (3.7%) oea 5 (3.1%) 6 (3.7%) HLT: Gastrointestinal atonic and hypornotility disorders NBC 4 (2.5%) 1 (0.6%) Constipation 3 (1 .9%) O 505O PRIMARY SYSTEM ORGAN CLASS Giarginlen/iiiiiiienafide HLGT: High Level Group Term Fixed Ratio Insulin HLT: High Level Term Combination Glargine Preferred Term. n(%) (N=161) (N=162) HLGT: Gastrointestinal signs and symptoms 18 (11.2%) 7 (4.3%) HLT: tic signs‘and symptoms 2 (1.2%) 1 (0.6%) Dyspepsia 2 (1.2%) l (0.6%) HLT: Flatulence, bloating and sion 1 (0.6%) 2 (1.2%) Abdominal distension 1 (0.6%) 2 (1.2%) HLT‘: Nausea and ng symptoms 11. (8.7%) 1 (0.6%) Nausea 12 (7.5%) 0‘ Vomiting l (2.5%) 1 (0.6%) Musculoskeletal and tive tissue disorders 2 (13.0%) 13 (8.0%) HLGTzeJoint disorders 6 (3.7%) 6 (3.7%) liLT: Joint related signs and symptoms A (2.5%) 3 (19%) Arthralgia 4 (2.5%) 3 (‘ .9%) FLT; Osteoarthropathies ‘ (0.6%) 2 (1.2%) rthritis (0.6%) 2 (1.2%) HLGT: Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) 3 (1.9%) 2 ( 2%) HLT: lntervertebral disc disorders NBC 2 (1 .2%) 2 (1.2%) lntervertebral disc disorder 1 (0.6%) 2 ( .2%) - HLGT: Musculoskeletal and connective tissue disorders NBC 10 (6.2%) 3 (1.9%) HLT: Musculoskeletal and connective tissue pain and discomfort 10 (6.2%) 3 ( .9%) Back pain 5 (3.1%) 2 (‘ 2%) Musculoskeletal pain 2 (1.2%) 1 (0.6%) Pain in extremity 6 (3.7%) 0 Renal and urinary disorders 1 (0.6%) 2 (1.2%) HLGT: Urolithiases 1 (0.6%) 2 (1.2%) HLT: Renal lithiasis 0 2 (1.2%) Nephrolithiasis 0 2 (1.2%) General disorders and administration site conditions 12 (7.5%) 5 (3.1%) HLGT: Administration site reactions 5‘ (3.1%) 1 (0.6%) HLT: Injection site reactions 5 (3.1%) 1 (0.6%) Injection site us 2 (1.2%) 0 HLGT: General system disorders NBC 8 (5.0%) 4 (2.5%) ' HLT: Asthenic conditions 7 (4.3%) 0 Asthenia 2 (1.2%) 0 e 5 (3.1%). O 5151 Insulin ARY SYS' EM ORGAN CLASS .

Glargine/Lixisenatide HLGT: High .evel Group Term Fixed Ratio Insulin HLT: High Level Term Combination Glargine Preferred Term n(%) (N=161) ) HLT: Oedema NEC . l (0.6%) 3 (1.9%) Oedema ‘ 0 2 (1.2%) Investigations 3 (1.9%) 5 (3.1%) I-ILGT: intestinal investigations 2 (1.2%) 2 (1.2%) HLT: Digestive enzymes 2 (1.2%) 2 (1.2%) Lipase increased 2 (1.2%) 1 (0.6%) Injury, poisoning and procedural complications 7 (4.3%) 11 (6.8%) HLGT: es NBC 2 (1.2%). 9 (5.6%) HLT: Skin injuries NBC 0 5 (3.1%) Contusion' O 2 (1.2%) Laceration ' 0 3 (1.9%) TEAS: Treatment emergent adverse event, SOC: System organ class) HLGT: High level group term, HLT: High level term, PT: Preferred term MedDRA 15.1 n (%) = number and percentage of patients with at least one JAE Note: Table sorted by SOC internationally agreed order and :ILGT, HLT, PT by alphabetic order Only SOC with at least one PT 21% in at least one group are presented 3.3.2 Deaths, serious treatment—emergent adverse events No deaths were reported in this study. The number of patients with treatment nt SAE was 9 (5.6%) in the combination group and 6 (3.7%) in the insulin glargine group, which were diStributed over a variety of SOCs Without a notable increase in any specific SOC (table 17).

Table 17 - Number (%) of ts with treatment emergent SAE presented by primary SOC, HLGT, HLT, and PT — Safety population PRIMARY SYST 43M ORGAN CLASS Glargin61Liirisenatide HLGT: High Level Group Term . Fixed Ratio Insulin- HLT: High Level Term Combination Glargine Preferred Term [n(%)] .

. (N=161) (N=1-62) Any TEAS 9 (5.6%) 6 (3.7%) Infections and infestations 1 (0.6%) 1 (0.6%) HLGT: Bacterial ious disorders - . l (0.6%) O HLT: Bacterial infections NBC l (0.6%) O Cellulitis 1 (0.6%) o 5252 PRIMARY SYST+1M ORGAN CLASS Glarginlfiififigenafide HLGT:- High Level Group Term Fixed Ratio Insulin BELT: High Level Term Combination Glargine Preferred Term [n(%)} (N=161) ) HLGT: infections — pathogen unspecified 0 1 (0.6%) HLT: Urinary tract infections 0 1 (0.6%) Urinary tract infection 0 1 (0.6%) Neoplasms , malignant and unspecified (incl cysts and polyps) l (0.6%) O HLGT: Reproductive neoplasms female malignant and unspecified 1 (0.6%) 0 HLT: n neoplasms malignant (excl germ cell) %) 0 1 i Ovaiian cancer 1 (0.6%) 0 Psychiatric disorders 0 l (0.6%) HLGT: Depressed mood disorders and disturbances O 1 (0.6%) HLT: Depressive disorders 0' 1 (0.6%) sion 0 1 (0.6%) Nervous system disorders 2 (1.2%) 1 (0.6%) HLGT: Neurological disorders NBC 0 1 (0.6%) HLT: Neurological signs and symptoms NBC 0 1 (0.6%) cope ' 0 1 (0.6%) HLGT: Peripheral neuropathies 1 (0.6%) 0 HLT: Chronic polyneuropathies 1 (0.6%) 0 Diabetic neuropathy 1 (0.6%) O HLGT: Spinal cord and nerve root disorders 1 (0.6%) O HLT: Lumbar spinal cord and nerve root disorders 1 (0.6%) 0 Sciatica 1 (0.6%) 0 Cardiac disorders 3 (1.9%) . 1 (0.6%) HLGT: Cardiac arrhythmias 1 (0.6%) 1 (0.6%) HLT: Rate and raythm discrders NBC 1 (0.6%) 0 Bradycardia l (0.6%) O HLT: enticular arrhythmias 0 1 (0.6%) Atrial fibrillation 0 1 (0.6%) HLGT: Coronary artery disorders 2 (1.2%) 0 HLT: Ischaemic coronary artery disorders 2 (1.2%) 0 Angina pecton's 1 (0.6%) 0 Angina unstable 1 (0.6%) O 5353 PRIMARY SYSTEM ORGAN CLASS Glarginldiiliirligenatide HLGT: High Level Group Term . Fixed Ratio lnsulin HLT: High Level Terrn Combination Glargine red Term [n(%)] (N=161) (N=162) Musculoskeletal and connective tissue disorders 2 (1.2%) 1 (0.6%) HLGT: Joint disorders O 1 (016%) HLT: Osteoarthropathies 0 l (0.6%) Osteoarthritis 0 1 (0.6%) HLGT: Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) 1 (0.6%) 0 BLT: Intervertebral disc disorders NBC 1 (0.6%) 0 Intervertebral disc protrusion 1 (0.6%) 0 HLGT: Musculoskeletal and connective tissue disorders NBC 1 (0.6%) 0 HLT: Musculoskeletal and tive tissue pain and discomfort 1 (0.6%) 0 Pain in extremity . . l (0.6%) 0 Renal and urinary disorders 1. (0.6%) 0 HLGT: Urolithiases 1 (0.6%) 0 HLT: Urinary tract lithiasis (excl renal) ' 1 (0.6%) 0 Calculus ureteric l (0.6%) 0 Investigations 0 1 (0.6%) HLGT: Cardiac and vascular investigations (excl enzyme tests) 0 1 (0.6%) FLT: ECG 1nvest1gations O l (0.6%) ECG signs ofrnyocardial ischaemia 0 1 (0.6%) Injury, poisoning and procedural cations 1 (0.6%) O HLGT: Bone andjoint injuries 1 (0.6%) 0 HLT: Upper limb fractures and ations 1 (0.6%) 0 Radius fracture 1 (0.6%) O \1/ SAE: Serious adverse event, SOC: System organ class, HLGT: High level group term, HLT: High level term, PT: Preferred term MedDRA 15.1 n (%) = number and percentage of patients With at least one treatment emergent SAE Note: Table sorted by SOC ationally agreed order and HLGT, HLT, PT by etic order 3.3.3 Adverse events leading to Withdrawal Six patients (3.7%) in the combination group discontinued treatment due to TEAES compared With none in the insulin glargine group (Table 18). For 2 of these patients, TEAEsleading to treatment tinuation were those from the gastrointestinal disorders SOC (nausea and/or vomiting). One patient with nausea and ng and 1 patient With nausea and headache discontinued the MP at days 66 and 53 and their last insulin daily dose was 52 U (liXisenatide 26ug) and 18 U (liXisenatide 911g), respectively. 5454 A patient with hypersensitivity discontinued the IMP on first dose day. This event was not positively adjudicated as an allergic reaction by ARAC. Confusional state and dizziness in each — patient were confirmed as not related to symptomatic hypoglycemia.

Table 18 ~ Number (%) of patients experiencing TEARS) leading to permanent treatment discontinuation by primary SOC, HLGT, HLT,’and PT during on—treatment period — Safety population PRIMARY SYS’ fiM ORGANCLASS Glarginl§figgenafide HLGT: High ‘ revel Group Term Fixed Ratio Insulin HLT: High Level Term Combination . Glargine Prefe "red Term [n(%)] (N=161) ) Any TEAE 6 (3 7%) o Neoplasms benign, ant and‘unspecified (incl cysts and ) 1 (0.6%) 0 HLGT: Reproductive neoplasms female malignant and unspecified 1 (0.6%) 0 HLT: Ovarian neoplasms malignant (excl germ cell) 1 (0.6%) 0. n cancer 1 (0.6%) 0 Immune system disorders 1 (0.6%) O HLGT: Allergic conditions l (0.6%) 0 HLT: Allergic conditions NBC 1 (0.6%) 0 Hypersensitivity 1 (0.6%) 0 at‘ic disorders 1 (0.6%) 0 HLGT: Deliria (incl confusion) 1 (0.6%) 0 ‘ I-TLT: Confusion and disorientation 1 (0.6%) 0 Confusional state 1 (0.6%) O Nervous system disorders 2 (1.2%) 0 HLGT: Headaches 1 (0.6%) 0 HLT: Headaches NBC 1 (0.6%) . 0 he 1 (0.6%) 0 HLGT: Neurological disorders NEC 1 (0.6%) 0 HLT: Neurological signs and symptoms NBC 1 (0.6%) 0 Dizziness l (0.6%) 0 Gastrointestinal disorders 2 (1 .2%)‘ 0 HLGT: Gastrointestinal signs and symptoms ~ 2 (1.2%) 0 HLT: Nausea and vomiting symptoms 2 (1.2%) 0 Nausea 2 (1.2%) 0 5555 ARY SYSTEM ORGAN CLASS Glargine/Lixisenatide HLGT: High Level Group Term Fixed Ratio Insulin HLT: High Level Term Combination Glargine Preferred Term [n(%)] (N=161) (N=162) Vomiting . 1 (0.6%) o TEAS: Treatment emergent adverse event) SOC: System organ c ass, HLGT: High level group term, HLT: High level term, PT: Preferred term » MedDRA 15,l n (% = number and percentage of patients With at least one TEAS leading to permanent treatment discontinuation Note: Table sorted by SOC internationally agreed order and HLGT, HLT, PT by alphabetic order Hypersensitivity: it was adjudicated as not allergic event by ARAC. 3.3.4 Other significant adverse events A total of 6 patients (5 patients in the combination group and 1 patient in the insulin glargine group) experienced injection site reactions (Table 19). None of these ons were considered serious or seVere or led to treatment discontinuation.

Table 19— Number (%) of_ patients experiencing injection site reactions during the TEAE period — Safety population Insulin Glargine/Li‘xisenat ide Fixed Ratio Event source Combination Insulin ne Preferred Term - ) (N=162) Any ion site reactions 5 (3.1%) l (0.6%) PTs coded from the investigator reported terms 5 (3.1%) l (0.6%) Injection site pruritus ' 2 (1.2%) 0 Injection site pain 1 (0.6%) l (0.6%) ->/ Injection site rash l (0.6%) 0 Injection site urticaria ‘ l (0.6%) 0 PTs coded from the ARAC diagnosis terms 1 (0.6%) 0 Injection site on 1 (0.6%) 0 ARAC=Allergic Reaction Assessment Committee. PT=Preferred Term. 5656 A total of 2 patients (1 [0.6%] in each group) reported 6 events positively adjudicated as allergic reactions by the ARAC With thesarne diagnosis of allergic rhinitis. None was adjudicated as ly related to the IMP (table 20). ' Table 20 ~ Number (%) of patients with events adjudicated as allergic reaction by ARAC during the . period ~ Safety tion Glargine/Lixisen Relationship to MedDRA coded term atide Fixed Ratio study treatment (PT) ARAC Combination Insulin Glargine (by ARAC) for ARAC diagnosis diagnosis (N=161) (N=162) Events adjudicated as an allergic on All by ARAC 1 (0.6%) 1 (0.6%) Rhinitis allergic ALLERGIC RHINITIS l (0.6%) 1 (0.6%) Events adjudicated as an allergic reaction Not related to IMP by ARAC l (0.6%) l (0.6%) Rhinitis allergic ALLERGIC RHINITIS l (06%) 1 (0.6%) ARAC = Allergic Reaction Assessment Committee. lMP=lnvestigational medicinal product. 5757 Per protocol, any increase in amylase and/or lipase above twice the upper limit of normal range (ULN) or in Calcitonin 220 pg/mL that had been confirmed by a repeat measurement was to be monitored and documented on a specific AB form. During treatment period, 3 ts (2 [1.2%] in the combination group and 1 [0.6%] in the insulin glargine group) had a TEAE of lipase increased'(> 2 ULN) and 1 patient (in the insulin glargine group) had a TEAE of amylase increased (> 2 ULN) that were reported on the specific AB form. No patients reported a TEAE of increased calcitonin (220 pg/mL).

The number of ts who had at least 1 value of lipase or amylase Z3 ULN, or at least 1 value of calcitonin 220 pg/ml during the on~treatment period was also summarized. One patient in the insulin glargine group’had at least 1 value of amylase 2 3 ULN, and 5 patients (4 in the combination group and 1 in the insulin glargine group) had at least 1 value of lipase 23 ULN. One patient in the insulin glargine group had 1 value of onin 220 pg/ml (but <50 pg/ml) with retested values within the normal range.

One patient in the combination group and one patient in the insulin glargine group had respectively two events (hospitalization for unstable angina and percutaneous ry intervention [PCI]) and one event (PCT) adjudicated as major cardiovascular events by cardiovascular events adjudication committee (CAC). 3.3.5 Other safety observation—Symptomatic Hypoglycemia Symptomatic hypoglycemia events (including documented, probable, and severe symptomatic ycernia) were reported in 40 (24.8%) patients treated with the combination compared to 40 (24.7%) insulin glargine treated patients. The number of symptomatic hypoglycemia events per patient—year was 1.11 in both ent groups. No severe matic hypoglycemia was reported in any group (Table 21).

The rate of documented symptomatic hypoglycemia with plasma glucose £70mg/dL (3.9 mmol/L) was similar in beth treatment groups (35 [21.7%] versus 37 [22.8%] in the combination and insulin ne groups, tively). For documented symptomatic hypoglycemia with plasma glucose dL (3.3 mmol/L) the rate washigher in the combination group versus the insulin ne group {20 (12.4%) versus 9 ].

Table 21 — Summary of symptomatic hypoglycemia recorded on the ted eCRF and meeting protocol definition during the TEAE period — Safety population Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine‘ Type (N=161) (N=162) Total patient years ' . 73.1 75.6 Symptomatic hypoglycemia .

Number of patients with events, n (%) ' 40 (24.8%) 40 (24.7%) Number of events ’ 81 84 - 5858 Insulin ne/Lixisenatide Fixed Ratio ation Insulin Glargine Type ‘ (N=161) (N=162) Number of events per 100 patient yearsa 110.8 111.1 Documented symptomatic hypoglycemia a glucose <=70 mg/dL [3.9 mmol/L]) Number of patients with events, n (%) 35 (21.7%). 37 (22.8%) Number of events 71 . 79 Number of events per 100 patient yearsa 97.1 104.5 Documented symptomatic hypoglycemia (plasma glucose <60 mg/dL [3.3 mmol/L]) Number of patients with events, n (%) 20 (12.4%) 9 (5.6%) Number of events 30 is Number of events per 100 patient years?1 41.0 23.8 Documented symptomatic hypoglycemia (plasma e <54 mg/dL [3.0 ]) Number of patients with events, n (%) 13 (8.1%) 4 (2.5%) Number of events 16 10 - Number of events per 100 patient yearsa 21.9 13.2 . le symptomatic hypoglycemia Number ofpatients with events, n (%) 9 (5.6%) 5 (3.1%) Number of events 10 Number of events per 100 patient yearsa 13.7 Severe symptomatic hypoglycemia Number of ts with events, n (%) 0 Number of events 0 . 0 Number of events per 100 patient years3 0.0 0.0 3: Calculated as (number of events*100 divided by total exposure + 3 days in patient years).

Symptomatic hypoglycemia = symptomatic hypoglycemia recorded on the dedicated eCRF and meeting protocol definition for severe, or documented, or probable symptomatic hypoglycemia. 5959 Example 2 A randemized, 30 week, activewcon‘treiied, openuiabei, Entreatment arm, paraffei—group muiticenter study comparing the efficacy and safety cf inertia giargr‘ae/ tixisenatide fixed ratie cembinatien te insulin giargme aierie arid ta lixisenatide aiene en tee 0f metfermirr in patients with i.

Cempeund cede: HOEQO‘l/AVEOOiO {siftitli‘z’ TlTUE 3e MAM E35 Title: A randomized, 30 week, active-controlled, open-label, 3-treatment arm, parallel-group multicenter study comparing the efficacy and safety of n glargine/ lixisenatide fixed ratio combination to insulin glargine alone and to lixisenatide alone on top of metformin in patients with T2DM Short Title: Efficacy and safety of insulin glargine/ lixisenatide fixed ratio combination versus insulin glargine alone and versus lixisenatide alone on top of metformin in patients with T2DM iDECZAL CQNQi'fiQN Therapeutic area MedDRA Preferred Term MedDRA classification code Nutritional and metabolic diseases Type 2 diabetes 10067585 smart" QEfidEC‘ftVES Primary: To compare the insulin glargine/lixisenatide fixed ratio combination versus lixisenatide and versus n ne (on top of metformin treatment) in HbAtc change from baseline to week 30.

Secondary: To compare the overall efficacy and safety of insulin glargine/lixisenatide fixed ratio combination versus n glargine and lixisenatide alone (on top of metformin treatment) over a 30 week treatment period in patients with type 2 diabetes Primary purpose: Treatment Primary focus: /Efficacy Scope of the trial: El Diagnosis 1:] laxis i2 Therapy E Efficacy Safety I: Pharmacodynamic g Pharmacokinetic 1:] Bioequivalence [:1 Dose response 1:! Pharmacogenetic El cogenomic Cl Pharmacoeconomic 6060 STUDY Qt‘ifiifiié Phase: Phase 3 Allocation: Randomized Masking: Open Label Design: Parallel Number of arms: ‘3 Arm Label Arm description Arm type Label in study Provide information specific to the arm — in particular detaiis on the Select “experimental" when schema WP and non-lii/iP administration {e.g. product, , frequency, the study compound is duration, condition of the e(s)) stered insulin insulin glargine/iixisenatide fixed ratio combination is injected Experimental giargine/lixisenatide aneously so. (under the skin) once daily (OD). Dose fixed ratio individually adjusted. Metformin treatment should be continued. combination Insulin giargine insulin giargine is injected subcutaneously so. (under the skin) once Active Comparator daily (OD). Dose individually adjusted. Metformin treatment should be continued.

Lixisenatide Lixisenatide is injected aneously so. (under the skin) once Active Comparator daily (OD). Starting dose will be iOpg, then increased to the 20pg maintenance dose after 2 weeks. Metiormin treatment should be continued.

The insulin glargine/lixisenatide fixed ratio combination comprises 100 U/mL insulin giargine and 50 pg/mL iixisenatide. The insulin giargine formulation (Lantus) ses 100 U/mi insulin giargine. The iixisenatide formulation ia) comprises 50 pg/ml iixisenatide (for administration of a dose of 10 pg iixisenatide) or 100 ug/mi iixisenatide (for administration of a dose of 20 pg iixisenatide). Metformin is stered in a dose of at least ”1.0 9/day or at least 1.5 g/day.

$"FUQV PGF’ULAWQN Population Gender Age Range Minimum Maximum El Healthy volunteers Both 18 Unit: Years Unit: Select Unit K Patients or E] NA (no limit) or ix NA (no limit) inclusion criteria: - Patients with type 2 diabetes mellitus diagnosed for at least 1 year before the screening visit, treated for at least 3 months prior to visit 1 with min alone or metiormin and a second oral anti-diabetic ent that can be a sulfonyiurea (SU) or a giinide, or a SGLT—Z inhibitor who are not tely controlled with this treatment; ~ Signed written informed consent 6161 Exclusion criteria: . Age under legal age of adulthood at screening visit; . HbAlc at screening visit: < 7.5% and > 10% for patients previously d with metformin alone, < 7.0% and > 9 % for patients previously treated with metformin and a second oral anti-diabetic treatment; ' = Pregnancy or lactation, women of childbearing potential with no effective contraceptive method; . Use of other oral or injectable glucose-lowering agents than stated in the inclusion ia in a period of 3 months prior to screening.

- Treatment with insulin more than 3 months ago (except for short'term ent due to intercurrent illness including gestational diabetes at the discretion of the trial physician) ° History of discontinuation of a previous treatment with a GLP-1 receptor agonist (GLP-i RA) due to safety/tolerabiiity issue or lack of efficacy; ~ Patient who has usly participated in any clinical trial with lixisenatide or the insulin giargine/lixisenatide fixed ratio combination or has previously received lixisenatide.

~ Any contraindication to metformin use, according to local labeling « Use of weight loss drugs within 3 months prior to screening visit. w Within the last 6 months prior to screening visit: history of stroke, myocardial infarction, unstable angina, or heart failure ing alization. Planned coronary, carotid or peripheral artery ularisation procedures to be performed during the study period.

- History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy already med), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery.

.. Personal or immediate family history of medullary thyroid cancer (MTC) or genetic ions that predispose to MTC (eg, multiple endocrine neoplasia syndromes).

. Uncontrolled or inadequately lled hypertension lic blood pressure above 180 mmHg or diastolic blood pressure above 95 mmHg) at screening visit 9 At screening visit, Body Mass index (BMI) less than or equal to 20 or above 35 kg/m2 » At screening visit amylase and/or lipase more than 3 times the upper limit of the normal (ULN) laboratory range, - ., At screening visit ALT or AST more than 3 ULN = At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L) Exclusion ia for randomization'at the end of the screening period: o HbAlc <7% or > 10% at visit4 (week 1); ~ Fasting Plasma glucose at visit 4 (week -1) >250mg/dL (13.9 ); . ll/letformin maximal tolerated dose < 1500 mg/day; . Amylase and/or lipase measured one week prior to randomization is >3 times ULN; 6262 Specific vulnerable populations: 1:] Women of bearing potential not using contraception E Women of child-bearing potential using contraception [:1 nt women [3 Nursing women [3 Emergency ion TQYAEW ‘EQ neuraee Qt: $L§SJECTSJPA$EEW8 ed I Enrolled Randomized" (Inform Consent Form signed) Planned number of subjects/patients 2200 1125 * treated for non randomized studies Approximate nunnber‘ot Subjects/patients persage range: Adults: 920 y: 205 (18-64 years) (i 65 years) reentcrszae PRGEUG?@ {tNVfiSTtGATEGNAL gs NSF»? iNVEfiTiQi-‘s’t'lflt‘tfim INN ifavailable Compound code Trade name Pharmaceutical form Route of administration or Sanofi compound only if available eg, tablet, capsule; eg. oral, intravenous, placebo solution. ,. intramuscular, subcutaneous...

Insulin HOE901/AVE0010 solution for injection subcutaneous Injection glargine/Iixisenatide (disposable self Insulin glargine HOE901 Lantus solution for injection subcutaneous Injection (disposable self Injector) Lixisenatide AVEOOI O Lyxumia solution for injection subcutaneous injection (disposable self injector) 6363 Eisiti‘rFiQii‘éTS Endpoint title Time frame for tion Assess a eg. change from baseline in a'parameter, time to a specific Enter the ints at which the measure is safety event, number of patients with prespecified event. specific assessed or the assessment duration ‘ issue? measurement y Endpoint Change in HbAic from baseline week 30 I:] Yes E] Yes [:1 Yes Secondary Endpoints Percentage of patients reaching HbAtc targets week 30 [3 Yes [:I Yes Change in 2—hour Post Prandial Glucose and in blood e week 30 E] Yes excursion during standardized meal test from baseline Change in body weight from baseline week 30 1:] Yes Change in 7-point Self Measured Plasma Glucose profiles from week 30 D Yes baseHne Change in daily dose of insulin glargine from baseline week 30 1:] Yes Change in FPG from baseline week 30 E] Yes Documented (plasma glucose less than or equal to 70 mg/dl) 30 weeks Yes symptomatic ycemia Severe symptomatic hypoglycemia 30 weeks [2 Yes l:| Yes StitfiafifiiQN Qt”: SKEW! estates Duration per subject/patient: approximately 37 weeks including 30 week treatment period

Claims (17)

CLAIMS :

1. Use of 5 (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) insulin ne or/and a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical ition for treating diabetes mellitus type 2 in a subject as add-on to treatment with metformin and/or a pharmaceutically acceptable salt thereof, 10 wherein compound (b) is present in a concentration of 100 U/ml, and compound (a) is present in a tration of 50 µg/ml.

2. The use of claim 1, wherein the composition is formulated to deliver a dose of 0.25 to 1.5 U/kg body weight insulin glargine.

3. The use of claim 1, wherein the composition is formulated to deliver a dose of 0.05 to 0.5 µg/kg body weight lixisenatide.

4. The use of any one of the claims 1 to 3, wherein the subject is obese.

5. The use of any one of the claims 1 to 4, wherein the diabetes mellitus type 2 is not adequately controlled with metformin alone.

6. The use of any one of the claims 1 to 5, wherein the subject has a HbA1c 25 value in the range of at least 7 %, at least 8 % or at least 9% at the onset of treatment with the composition.

7. The use of any one of the claims 1 to 6, wherein the subject has a fasting plasma glucose concentration of at least 7 mmol/L, at least 8 mmol/L, at 30 least 9 , at least 10 mmol/L, or at least 11 mmol/L at the onset of treatment with the composition.

8. The use of any one of the claims 1 to 7, wherein the subject has a selfmonitored plasma e concentration of at least 8 mmol/L, at least 9 17793690_1 (GHMatters) P41292NZ00 mmol/L, at least 10 mmol/L, or at least 11 mmol/L at the onset of treatment with the composition. 5

9. The use of any one of the claims 1 to 8, wherein the subject has a 2-hour postprandial plasma glucose of at least 12 mmol/L, at least 13 mmol/L, at least 14 mmol/L, at least 15 mmol/L, at least 16 mmol/L, or at least 17 mmol/L at the onset of treatment with the composition.

10 10. The use of any one of the claims 1 to 9, wherein the subject has a 2-hour postprandial plasma e excursion of at least 5 mmol/L, at least 5.5 , at least 6 mmol/L, at least 6.5 mmol/L, or at least 7 mmol/L at the onset of treatment with the composition. 15

11. The use of any one of the claims 1 to 10, wherein the subject does not receive a GLP-1 receptor t or/and an insulin.

12. The use of any one of the claims 1 to 11, wherein the composition is formulated to effect parenteral administration.

13. The use of any one of the claims 1 to 12, wherein the subject is at least 50 years old.

14. The use of any one of the claims 1 to 13, wherein the subject has a body 25 mass index of at least 30 kg/m2, at least 31 kg/m2, at least 32 kg/m2 or at least 33 kg/m2.

15. The use of any one of the claims 1 to 14, wherein the diabetes mellitus type 2 in the t is inadequately controlled by at least 1.5 g/day of metformin.

16. The use of claim 1, with the proviso that the composition is not an on-site mixed ition. 17793690_1 (GHMatters) P41292NZ00

17. The use of claims 1 or 16, wherein the composition is provided within a ner. 17793690_1 (GHMatters) P41292NZ00