NZ734595B2 - Treatment of pediatric type 2 diabetes mellitus patients with lixisenatide - Google Patents

Abstract

The present invention refers to lixisenatide for use in pediatrics. Specifically, the use of lixisenatide to treat Type 2 diabetes mellitus (T2DM) in pediatric patients, where the treatment may be used as an add-on therapy in conjunction with the administration of known T2DM medicament Metformin.

Description

TREATMENT OF PEDIATRIC TYPE 2 DIABETES US PATIENTS WITH LIXISENATIDE Description It is to be understood that if any prior art publication is referred to herein, such reference does not constitute an ion that the publication forms a part of the common general knowledge in the art in New Zealand or any other country.

Subject of the present invention is desPro36 Exendin-4(1-39)-Lys 6-NH 2 (AVE0010, lixisenatide) or/and a pharmaceutically able salt thereof, for use in pediatrics. Yet r subject of the present invention is a pharmaceutical combination for use in pediatrics, said combination comprising (a) lixisenatide or/and a pharmaceutically able salt thereof, and (b) metformin or/and a pharmaceutically acceptable salt thereof.

Yet r aspect is a method for treatment of a pediatric patient, said method comprising administering lixisenatide or/and a pharmaceutically acceptable salt thereof, optionally in ation with metformin, to a pediatric t in need thereof.

In a healthy person the release of insulin by the pancreas is strictly coupled to the concentration of blood glucose. An increased level of blood glucose, as appears after meals, is rapidly 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 insulinsensitive organs and tissues and to keep the hepatic glucose production at a low level at night.

In contrast to type 1 diabetes, there is not generally a lack of insulin in type 2 diabetes mellitus 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 iabetic drugs.

An increased glucose level in the blood over several years without l symptoms represents a significant health risk. It could clearly be shown by the large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) 18464995_1 ters) P43144NZ00 that chronically increased levels of blood glucose are a main reason for the development of diabetes complications. Examples for diabetes complications are micro and macrovascular damages that possibly manifest themselves in retinopathies, nephropathies or neuropathies and lead to ess, 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 oven/veight patients suffering from type 2 diabetes mellitus, e.g. patients with a body mass index (BMI) 2 30 kg/mz. In these patients the risks of diabetes p with the risks of oven/veight, leading e.g. to an increase of cardiovascular diseases compared to type 2 diabetes us patients being of a normal weight.

Until recently, type 2 diabetes mellitus (T2DM) was almost exclusively an adult disease. ding with the increasing prevalence of obesity in children, the incidence of T2DM in children and adolescents has markedly increased to the point that it ts for as many as one third of all the new cases of T2DM sed in adolescent.

Children/adolescents with T2DM are usually diagnosed over the age of 10 years, in middle to late puberty, when due to physiological changes in the GH/lGF-1 axis insulin resistance develops. Like in adults, the incidence of type 2 diabetes in children/adolescents is highest in some ethnic populations (e.g. American Indians, African an, Asian/pacific Islander and Hispanics) (Canadian Diabetes Association Clinical Practice ines _xpert Committee, Type 2 es in Children and cents, 2008 Clinical ce Guidelines, 8162—8167). iabetes is a therapeutic area for which the EMA Paediatric Working Party considers that research and development of medicinal products for children should be med. Type 2 diabetes may have an earlier and more aggressive course in pediatric patients; therefore, they are likely to be at higher risk for developing cations and need the best le ic l in the early stage of their e.

T2DM in children differs from adults in a number of ways that have an important impact on potential treatment. Puberty appears to play a major role in the development of type 2 diabetes in children. During y, there is increased resistance to the action of insulin, resulting in hyperinsulinemia.

Growth hormones have been considered as candidates for causing insulin resistance during y. The mean growth e levels increase transiently during puberty coincidental with the decrease in insulin .

Given this information, it is not surprising that the peak age at presentation of type 2 diabetes in children coincides with the usual age of mid-puberty. In an individual who has a genetic position for insulin resistance, compounded with environmental risk re, the additional burden of insulin resistance during puberty may tip the balance from a state of compensated hyperinsulinemia with normal glucose tolerance to inadequate insulin secretion and glucose intolerance that continues beyond puberty (American Diabetes ation, Diabetes Care 2000, 23(3): 381-389). in the US, about 12% of type 2 pediatric diabetes mellitus patients received metformin monotherapy and about 34 % received insulin monotherapy Dombrowsky and Barrett, Type II Diabetes Mellitus in en: Analysis of Drevalence Based on the Pediatric Heath Information System (PI-t8) Database, American College of Clinical Pharmacology Annual Meeting September 22nd — 24th 2013, Bethesda, Maryland). In many pediatric type 2 diabetes mellitus patients, progression of the disease is rapid, and control of hyperglycaemia may become insufficient even at maximal tolerated doses of metformtn. -lowever there are no reported studies describing the efficacy of GLP-1 analogs in the pediatric population.

Metformin is a biguanide hypoglycemic agent used in the treatment of non— insulin-dependent diabetes mellitus (type 2 diabetes mellitus) not responding to dietary modification. Metformin es glycemic control by improving n sensitivity and decreasing intestinal absorption of glucose. Metformin is usually administered orally. However, control of type 2 diabetes mellitus in obese patients by metformin may be insufficient. Thus, in these patients, additional measures for controlling type 2 diabetes mellitus may be required.

Metformin is the ational nonproprietary name of 1,1—dimethylbiguanide (CAS number 657-24—9).

The compound desPro35Exendin-4(1-39)~Lys6—NH2(AVEOO1O, lixisenatide) is a derivat've of Exendin—4. AVEOO1O is disclosed as SEQID NO:93 in wo 156: SEQ ID NO: 1: lix'senatide (44 amino acids) H—G—E—G-T—F-T—S—D-L—S~K—Q-M—E-E-E—A-V—R—L-F—I-f3—W—L-K—N—G—G—P-S—S-G— A-P-P~S-K-K-K-K—-<—K—NH2 SEQ | NO: 2: exendin-4 (39 am'no acids) H-G—E-G—T-F-T-S- )-L—S-K—Q—M-E~ 3~E-A-V-R—L-F—I-E—W—L-K—N—G—G—P—S—S-G— A—P—P—P—S—NHZ Exendins are a group of peptides which can lower blood glucose concentration. The Exendin ue natide is characterised by C- terminal truncation of the native Exendin—4 sequence. Lixisenatide comprises six C-terminal lysine residues not present in Exendin-4.

Lixisenatide is also termed des-38—proline—exendin—4(Heloderma suspecfum)- (1 —39)-peptidylpenta—L—lysyl-L—lysinamide (CAS number 3203673).

The aim of the present ion can be seen in the improvement of anti- diabetic treatment in en and adolescents suffering from diabetes mellitus, in particular from type 2 diabetes me litus.

In Examples 1 and 2 of the present 'on, after a standardized liquid breakfast in ’12 pediatric patients with Type 2 Diabetes mellitus (TZDM) with a mean HbA1C of 8.65% and mean body weight of 84.7 kg, a non-significant decrease in plasma glucose cted plasma glucose AUCO;30h_4;30h and plasma glucose AUCo;3oh_ 430),) was observed with single doses of Iixisenatide and 10 pg compared to placebo. In contrast, single doses of lixisenatide 5 and 10 pg icantly reduced plasma glucose (corrected plasma glucose AUC0;30h-4;30h and plasma glucose AUC0;30h4;30h) compared to placebo in 12 adult patients with T2DM. Lixisenatide exposure was r for both dose groups in the evaluable pediatric patients, s in adult patients, the Iixisenatide exposure dose-proportionally increased. In pediatric patients, the exposure was similar to that in adults for Iixisenatide 5 pg, but lower for lixisenatide 10 pg. Single doses of lixisenatide 5 and 10 pg were safe and well tolerated in both, pediatric and adult patients in this study of short duration.

In conclusion, Examples 1 and 2 demonstrated able pharmacokinetic (PK) and pharmacodynamic (PD) profiles in pediatric and adults patients at a dose of 5 pg, as well as no unexpected safety results.

Examples 1 and 2 of the present invention confirm that adult patients have a different pathophysiology compared with children and cents. The response to a standardized liquid breakfast ed in pediatric type 2 diabetes mellitus patients from that of adult patients. In the pediatric control population (placebo group), the peak insulin concentration was observed about one hour after the test meal (Figure 12), followed by a rapid decline. In the adult control population (placebo group), the andial insulin peak was broader. The peak insulin concentration was observed about 2 hours after the test meal e 11). A similar difference was observed in the postprandial C-peptide concentration (Figures 13 and; 14).

In line with these findings, differences were identified in the effects of natide in the ric patients compared with the effects obtained in the adult patient population. The described differences in time course of postprandial insulin and ide secretion found in the placebo groups were also observed under Iixisenatide.

RECTIFIED SHEET (RULE 91) lSA/EP The exposure of lixisenatide in pediatric patients lixisenatide was smaller than in adults at doses of 10 pg es 15 and 16). The reduction of postprandial plasma glucose (PPG) by treatment with lixisenatide was smaller than in adult patients, and, due to the small number of patients, not significant (Figures 5 to 8).

Surprisingly, at a dose of 5 pg, lixisenatide exhibited a larger reduction in plasma glucacon level than in adult patients (Figures 9 and 10).

In summary, the results of Example 2 indicate ences in the pathophysiology of pediatric type 2 diabetes mellitus patients and adult patients. The fact that lixisenatide can reduce postprandial plasma glucose, postprandial glucagon and insulin secretion in pediatric patients tes that natide is effective in the treatment of this patient group.

Example 3 of the present invention describes a randomized, double-blind, placebo-controlled, dose escalation, study on safety, cokinetics and pharmacodynamics of lixisenatide in pediatric patients with type 2 diabetes not adequately controlled with metformin and/or basal insulin.

A first aspect of the present invention is lixisenatide or/and a pharmaceutically acceptable salt thereof, for use in pediatrics.

Another aspect of the present invention is a pharmaceutical combination for use in rics, said combination comprising (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) min or/and a pharmaceutically acceptable salt thereof.

Yet another aspect of the present ion is a ceutical combination for use in pediatrics, said combination comprising (a) lixisenatide or/and a ceutically acceptable salt thereof, (b) metformin or/and a pharmaceutically acceptable salt thereof, and (c) a basal insulin or/and a pharmaceutically acceptable salt thereof.

RECTIFIED SHEET (RULE 91) ISA/EP Yet another aspect of the present invention is a pharmaceutical combination for use in pediatrics, said combination comprising (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) a basal n or/and a pharmaceutically able salt thereof.

As used herein, "to be treated according to the present invention", ”treatment according to the present invention", or "pediatric treatment according to the present invention" relates to the treatment of pediatric patients, as d herein, by (i) lixisenatide or/and a pharmaceutically acceptable salt thereof, or (ii) the pharmaceutical combination as described .

The patient in need of the pediatric treatment according to the t invention by may have an age of at least 10 years.

The patient in need of the pediatric treatment according to the present invention as described herein may have an age of less than 18 years.

It is preferred that the patient in need of the pediatric treatment according to the present invention as described herein may have (a) an age of at least 10 years, and (b) and age of less than 18 years.

The patient in need of the pediatric treatment according to the present ion as described herein may suffer from type 2 es mellitus.

The pediatric patient to be treated according to the present ion may be a subject suffering from type 2 diabetes mellitus, wherein type 2 diabetes mellitus is not adequately controlled by treatment with metformin monotherapy, for instance with a dose of at least 1.0 g/day metformin or at least 1.5 g/day metformin for 3 months, or/and a dose of at the maximum 2.0 g/day min for 3 months.

The pediatric patient to be treated according to the t invention may be a subject suffering from type 2 es mellitus, wherein type 2 diabetes mellitus is not adequately controlled by treatment with a basal insulin or/and metformin, for instance with a dose of at least 1.0 g/day metformin or at least 1.5 g/day min for 3 months, or/and a dose of at the maximum 2.0 g/day metformin for 3 months.

The pediatric patient to be treated according to the present invention may be a subject ing from type 2 diabetes mellitus, wherein type 2 diabetes mellitus is not adequately controlled by treatment with a basal insulin monotherapy. in the present invention, "not tely controlled" by the ent with metformin monotherapy (treatment with metformin alone) means that min monotherapy is not sufficient to remove the symptoms of diabetes mellitus. In particular, "not adequately controlled" by the treatment with metformin monotherapy means that the patient does not reach normoglycemic values in terms of, for example, postprandial plasma glucose concentration, glucose excursion or/and fasting plasma glucose concentration. in the present invention, "not adequately controlled" by the treatment with metformin or/and a basal insulin means that this therapy alone is not sufficient to remove the symptoms of diabetes mellitus. In ular, "not adequately controlled" by the treatment with metformin or/and a basal insulin means that the patient does not reach normoglycemic values in terms of, for example, postprandial plasma glucose concentration, glucose excursion or/and fasting plasma glucose concentration.

In the t invention, "not adequately controlled" by the treatment with a basal insulin monotherapy (treatment with a basal insulin alone) means that this therapy alone is not sufficient to remove the symptoms of diabetes mellitus. in ular, "not tely controlled" by the treatment with a basal insulin monotherapy means that the patient does not reach normoglycemic values in terms of, for example, postprandial plasma glucose tration, glucose ion or/and fasting plasma glucose concentration.

The term "not adequately controlled" by the treatment with metformin monotherapy in ular relates to the period before onset of treatment according to the present invention. It can be diagnosed before onset of the treatment according to the present ion if monotherapy with metformin adequately ls the type 2 diabetes mellitus or not. For example, such diagnosis may be performed within 1 months, within 2 months or within 3 months before onset of the therapy of the present invention.

The term "not adequately controlled" by the treatment with metformin or/and a basal insulin in particular relates to the period before onset of treatment according to the present invention. it can be sed before onset of the treatment according to the present invention if the therapy with metformin or/and a basal insulin adequately controls the type 2 diabetes mellitus or not.

For example, such sis may be performed within 1 months, within 2 months or within 3 months before onset of the y of the present invenfion.

The term "not adequately controlled" by the treatment with a basal n monotherapy in particular relates to the period before onset of treatment according to the present invention. It can be diagnosed before onset of the treatment according to the present ion if the therapy with a basal n monotherapy adequately controls the type 2 diabetes mellitus or not. For example, such diagnosis may be performed within 1 months, within 2 months or within 3 months before onset of the therapy of the present invention.

By the treatment according to the present invention, adequate control of type 2 diabetes mellitus may be achieved in pediatric patients not adequately controlled with metformin monotherapy.

By the treatment according to the present ion, adequate control of type 2 es mellitus may be achieved in pediatric patients not adequately controlled with metformin or/and a basai insulin.

By the treatment according to the present invention, adequate control of type 2 diabetes mellitus may be achieved in pediatric patients not adequately controiied with a basai n monotherapy.

The pediatric patient suffering from type 2 diabetes mellitus to be treated according to the present invention may be obese. A t can be considered as obese if the body mass index is at least 30 kg/mz. In the present invention, an obese pediatric t may have a body mass index of at least 30 kg/m2 or at least 31 kg/mz. It is preferred that that the pediatric patient has a body mass index of at least 31 kg/mz.

The pediatric patient ing from type 2 diabetes mellitus to be treated according to the present invention preferabiy does not receive an antidiabetic treatment by insulin or/and related compounds.

The pediatric patient suffering from type 2 diabetes mellitus to be treated according to the present invention may suffer from type 2 diabetes mellitus for at least three months. in particular, in the pediatric patient to be treated, type 2 diabetes mellitus has been sed for at least three months before onset of therapy of the present invention. in the present invention, a ric patient may have a HbAlc value in the range of 7 % to 10%, or 7% to 9.9%. In particular the pediatric patient to be treated may have a l—le1C value of at least about 7 %, at least about 7.5 %, at least about 8 %, at least about 8.5 %, at least about 8.65 %, or at least about 9 %.

In particular, in a pediatric patient ing metformin monotherapy (in ular before onset of therapy according to the present invention), a bAtc value in the range of 7 % to 10% or 7% to 9.9%, or a HbA1C value of at least about 7 %, at ieast about 7.5 %, at least about 8 %, at least about 8.5 %, at least about 8.65 %, or at least about 9 % tes that the type 2 diabetes mellitus is not adequately controlled by metformin monotherapy.

In particular, in a pediatric patient ing metformin or/and a basal insulin (in particular before onset of therapy according to the present invention), a -ibA1c value in the range of 7 % to 10% or 7% to 9.9%, or a -le1c value of at least about 7 %, at least about 7.5 %, at least about 8 %, at least about 8.5 %, at least about 8.65 %, or at least about 9 % tes that the type 2 diabetes mellitus is not adequately controlled by metformin or/and a basal insulin.

In particular, in a pediatric patient receiving a basal insulin monotherapy (in particular before onset of therapy according to the present invention), a HbA1c value in the range of 7 % to 10% or 7% to 9.9%, or a HbA1C value of at least about 7 %, at least about 7.5 %, at least about 8 %, at least about 8.5 %, at least about 8.65 %, or at least about 9 % indicates that the type 2 diabetes mellitus is not adequately controlled by a basal insulin monotherapy.

In the present invention, normoglycemic values are blood glucose concentrations of in particular 60 — 140 mg/dl (corresponding to 3.3 to 7.8 mmol/L). This range refers in ular to biood e concentrations under fasting conditions and postprandial conditions.

Criteria for a type 2 diabetes mellitus diagnosis include: - the fasting plasma e concentration (FPG) is 2 7.0 mmol/L (126 mg/dl), or - the post challenge plasma glucose concentration is > 11.1 mmol/L (200 mg/dl), med as bed by the World -lea|th Organization (Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Part 1: Diagnosis and Classification of Diabetes Mellitus.

D/NCS/992. Geneva; 1999), using a glucose load containing the equivalent of 75 g ous glucose dissolved in water, or - symptoms of diabetes and a casual plasma glucose 2 200 mg/di (11.1 mmol/L).

These criteria are described in the Global lDF/lSPAD Guideline for es in Childhood and Adolescence (international Diabetes Federation, ISBN 2— 930229—72—1).

The sis of Type 2 Diabetes should not be based on a single plasma glucose concentration. Diagnosis may require continued observation with fasting and/or andial blood glucose levels and/or an oral glucose tolerance test.

According to Craig ( ediatric Diabetes 2014: pl. 20): 4—17), fasting plasma glucose (FPG) and post nge (postload) e can be classified as follows: — FPG < 5.6 mmol/L (100 mg/dL) = normal fasting glucose concentration.

— FPG 5.6 to 6.9 mmol/_ (100—125 mg/dL) = impaired fasting glucose concentration.

- FPG 2 7.0 mmol/L (126 mg/dL) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above) The corresponding categories when the Oral Glucose Tolerance Test (OGTT) is used are as s: - Two hour postload glucose < 7.8 mmol/L (140 mg/dL) = normal glucose tolerance.

- Two hour postload glucose 7.8 to <11.1mmol/L (140—200 mg/dL) = impaired glucose tolerance.

— Two hour postload glucose 2 11.1 mmol/L (200 mg/dL) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above).

Impaired glucose tolerance (IGT) and impaired fasting glucose concentration (IFG) are intermediate stages in the natural history of disordered ydrate lism between normal glucose tasis and In the present invention, normoglycemic glucose concentrations can include impaired glucose concentrations, as described herein.

In the present invention, normoglycemic values of fasting plasma e are blood glucose concentrations of in particular < 5.6 mmol/L or < 7.0 mmol/L.

In the present invention, normoglycemic values of postprandial plasma glucose, as defined herein, are blood glucose concentrations of in ular <7.8 mmol/L or < 11.1 mmol/L.

The ric patient to be treated according to the present invention may have a 2 hours postprandial plasma e concentration of at least 11.1 , at least 12 mmol/L, or at least 13 mmol/L. These plasma glucose concentrations exceed normoglycemic concentrations.

In particular, in a pediatric patient receiving metformin monotherapy (in particular before onset of therapy according to the present ion), a 2 hours postprandial plasma concentration of at least 11.1 mmol/L, at least 12 mmol/L or at least 13 mmol/L indicates that the type 2 diabetes mellitus is not adequately controlled by metformin monotherapy.

In particular, in a pediatric patient receiving metformin or/and a basal n (in particular before onset of therapy according to the present invention), a 2 hours postprandial plasma concentration of at least 11.1 mmoI/L, at least 12 mmol/= or at least 13 mmol/L indicates that the type 2 diabetes mellitus is not adequately controlled by metformin or/and a basal insulin.

In particular, in a pediatric patient receiving a basal insulin monotherapy (in particular before onset of therapy according to the present invention), a 2 hours postprandial plasma concentration of at least 11.1 mmol/L, at least 12 mmol/L or at least 13 mmol/L indicates that the type 2 diabetes mellitus is not tely controlled by a basal insulin monotherapy.

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

Determination of postprandial plasma glucose is well-known (see, eg. Crapo et al., Diabetes, 1977, 26(12):1178—1183). A typical standardized ast suitable for exposure to glucose under experimental conditions in a meal test is described in the Appendix of e 2.

The pediatric patient to be treated according to the invention may have a glucose excursion of at least 3 mmol/L, at least 3.5 mmol/L or at least 3.65 mmol/L. In the t invention, the glucose excursion is in particular the difference of the 2 hours andial plasma glucose concentration and the plasma glucose concentration prior to a meal test, eg. the plasma glucose concentration 30 minutes prior to a meal test.

In particular, in a pediatric patient ing metformin monotherapy (in ular before onset of therapy according to the present invention), a glucose excursion of at least 3 mmol/L, at least 3.5 mmol/L or at least 3.65 mmol/_ indicates that the type 2 diabetes mellitus is not adequately contro led by min monotherapy ln part'cular, in a pediatric patient receiving min or/and a basal insulin (in particular before onset of y according to the present invention), a glucose excursion of at least 3 mmol/L, at least 3.5 mmol/_ or at least 3.65 mmol/_ indicates that the type 2 diabetes mellitus is not adequately contro led by metformin or/and a basal insulin.

In particular, in a pediatric patient receiving a basal insulin erapy (in particular before onset of therapy according to the present invention), a glucose excursion of at least 3 mmol/L, at least 3.5 mmol/L or at least 3.65 mmol/L indicates that the type 2 diabetes mellitus is not adequately controlled by a basal insulin monotherapy.

The pediatric patient to be treated ing to the invention may have a fasting plasma glucose concentration of at least 8 mmol/L, or at least 8,5 mmol/L. These plasma glucose concentrations exceed normoglycemic concentrations.

In particular, in a pediatric patient receiving mettormin monotherapy (in particular before onset of therapy according to the present ion), a fasting plasma glucose tration of at least 8 mmol/L, or at least 8,5 mmol/ tes that the type 2 diabetes mellitus is not adequately contro led by metformin erapy. ln part'cular, in a pediatric patient receiving metformin or/and a basal insulin (in particular before onset of therapy according to the present invention), a fasting plasma glucose tration of at least 8 mmol/L, or at least 8,5 mmol/L indicates that the type 2 diabetes mellitus is not adequately controlled by metformin or/and a basal insulin. in particular, in a pediatric patient receiving basal insulin monotherapy (in particular before onset of therapy according to the present invention), a fasting plasma glucose concentration of at least 8 mmol/L, or at least 8,5 mmoi/L indicates that the type 2 diabetes us is not tely controlled by basal insulin monotherapy.

The pediatric t to be treated according to the invention may have a C~ peptide plasma concentration of at least 1.2 nmol/. in fasting conditions.

The pediatric patient to be treated ing to the invention may have a plasma glucagon level of at least 140 ng/L in fasting conditions.

In another aspect of the present ion, (i) lixisenatide or/and a pharmaceutically acceptable salt thereof, or (ii) the combination as described herein can be used for improving (i.e. reducing) the 2 hours postprandial plasma glucose in a pediatric patient suffering from type 2 diabetes mellitus.

Reduction means in particular that the 2 hours postprandial plasma glucose concentration reaches normoglycemic values or at least approaches these values. n another aspect of the present invention, (i) natide or/and a pharmaceutically acceptable salt thereof, or (ii) the combination as bed werein can be used for improving (i.e. reducing) the glucose excursion in a pediatric patient suffering from type 2 diabetes mellitus. ion means in particular that the glucose excursion reaches normoglycemic values or at east approaches these values. n another aspect of the present invention, (i) lixisenatide or/and a ceutically acceptable salt thereof, or (ii) the combination as described herein can be used for improving (i.e. reducing) the plasma glucagon concentration in a pediatric patient suffering from type 2 diabetes us.

Lixisenatide or/and a pharmaceutically acceptable salt thereof, or the ation of the present invention can be used in the treatment of one or more of the medical indications described herein, for example in treatment of type 2 diabetes mellitus patients, as described herein, or for conditions associated with type 2 diabetes mellitus, such as for the improvement of glucose excursion, for improvement of the andial plasma e concentration, or/and for improvement of plasma on concentration.

The plasma glucagon concentration, as used , is in particular the ' postprandial plasma glucagon concentration. in the present invention, metformin includes pharmaceutically acceptable salts thereof. The person d in the art knows suitable pharmaceutically acceptable salts of metformin. in the present invention, metformin can be administered ing to commonly known administration protocols of metformin in accordance with the terms of ing authorization. Metformin can be administered to patients from 10 years. For example, metformin can be administrated once daily, twice daily or three times a day. In particular, the metformin dose applied before the onset of the y as disclosed herein is ued in combination with lixisenatide or/and a pharmaceutically acceptable salt thereof, as disclosed herein.

In the present invention, metformin may be administered orally. The skilled person knows formulations of metformin suitable for treatment of type 2 diabetes mellitus by oral administration. Metformin may be administered to a pediatric patient in need thereof, in an amount ient 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. Metformin may be administered in a dose of at the m of 2.0 g/day. The daily metformin dose can be d into 2 or three separate doses. 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 carriers, adjuvants, or/and auxiliary substances.

In the present invention, lixisenatide or/and a pharmaceutically acceptable salt may be stered in an add—on therapy to administration of metformin. ln the t invention, the terms "add-on", "add-on treatment" and "add—on therapy" can relate to treatment according to the present invention with metformin and lixisenatide.

In the present invention, the terms "add-on", "add-on treatment" and n therapy" can also relate to treatment according to the present invention with a basal insulin or/and metformin, and lixisenatide. in the present invention, the terms "add-on" n treatment" and "add-on therapy" can also relate to ent according to the t invention with a basal insulin and lixisenatide.

Metformin, natide or/and the basal insulin each may be administered in a once—a-day-dosage. Metformin, the basal insulin and lixisenatide may be administered by different administration routes. Metformin may be administered orally, and lixisenatide and the basal insulin may be administered parenterally. in particular, "add—on add—on treatment" and "add—on therapy" mean that the dose of metformin administered before the onset of the treatment with lixisenatide or/and a pharmaceutically acceptable salt thereof, as disclosed herein, is continued in combination with lixisenatide or/and a ceutically acceptable salt f.

In particular, "add—on", n treatment” and "add-on therapy" mean that the dose of the basal insulin administered before the onset of the treatment with natide or/and a ceutically acceptable salt thereof, as disclosed herein, is continued in combination with lixisenatide or/and the pharmaceutically acceptabie salt thereof. Alternatively, the dose of the basal insulin may be reduced in combination with lixisenatide or/and the pharmaceutically acceptable salt thereof; in the present invention, lixisenatide includes pharmaceutically acceptable salts thereof. The person d in the art knows suitable pharmaceutically acceptable salts of lixisenatide. A preferred pharmaceutically acceptable salt of lixisenatide employed in the present invention is the acetate salt of lixisenatide.

In the present invention, lixisenatide or/and the pharmaceutically acceptable sait thereof may be administered to a pediatric patient in need thereof, in an amount sufficient to induce a therapeutic effect. in the present invention, lixisenatide or/and the pharmaceutically acceptable salt thereof may be formulated with suitable pharmaceutically acceptable carriers, adjuvants, or/and auxiliary nces.

Lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered parenterally, e.g. by injection (such as by intramuscular or by subcutaneous injection). Suitable ion devices, for instance the so—cailed "pens" comprising a cartridge comprising the active ingredient, and an injection needle, are known. ixisenatide or/and a pharmaceutically acceptable salt thereof may be administered in a suitable amount, for instance in an amount in the range of 5 pg to 10 pg per dose.

In the present invention, lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered in a daily dose in the range of 5 to 10 pg.

Lixisenatide or/and a pharmaceutically acceptable salt thereof may be administered by one injection per day. Lixisenatide or/and a pharmaceutically acceptable salt f may be administered about 30 min before breakfast.

In the present invention, lixisenatide or/and a ceutically acceptable salt f may be provided in a liquid composition, which ably is an aqueous formulation. it is preferred that the liquid composition is suitable for eral administration, in particular for injection. The skilled person knows such liquid compositions of natide. A liquid composition of the present invention may have an acidic or a physiologic pH. An acidic pH preferably is in the range of pH 1 — 6.8, p-l 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 d acid (typically HCI) or pharmaceutically acceptable diluted base (typically NaOH).

The liquid composition comprising lixisenatide or/and a pharmaceuticaliy acceptable salt thereof may comprise a suitable preservative. A suitable preservative may be ed from , m-cresol, benzyl alcohol and p- hydroxybenzoic acid ester. A preferred preservative is m-cresol.

The liquid composition comprising lixisenatide or/and a pharmaceutically acceptable salt thereof may comprise a tonicity agent. A suitable tonicity agent may be ed from glycerol, lactose, ol, mannitol, glucose, NaCl, calcium or magnesium containing compounds such as CaClz. The » concentration of glycerol, lactose, sorbitol, mannitol and glucose may be in the range of 100 — 250 mM. The concentration of NaCl may be up to 150 mM. A preferred tonicity agent is glycerol.

The liquid composition comprising natide or/and a ceutically acceptable salt thereof may comprise methionine from 0.5 ug/mL to 20 ug/mL, preferably from 1 pg /ml to 5 pg/ml. Preferably, the liquid composition comprises L—methionine.

In the present invention, the basal insulin includes pharmaceutically acceptable salts f. The person skilled in the art knows suitable ceutically acceptable salts. in the present invention, the basal insulin or/and the pharmaceutically acceptable salt thereof may be administered to a pediatric patient in need thereof, in an amount sufficient to induce a eutic effect.

In the t invention, the basal insulin or/and the pharmaceutically acceptable salt thereof may be ated with suitable pharmaceutically acceptable carriers, adjuvants, or/and auxiliary substances.

The basal insulin or/and a pharmaceutically acceptable salt thereof may be administered parenterally, e.g. by injection (such as by intramuscular or by subcutaneous injection). Suitable injection devices, for instance the led "pens" comprising a cartridge comprising the active ingredient, and an injection needle, are known.

A further aspect of the present invention is a method of ric treatment, said method comprising administering to a patient in need of a pediatric treatment, lixisenatide or/and a pharmaceutically acceptable salt thereof.

In this method of treatment, the ric t is a patient as bed herein. In particular, the pediatric patient suffers from type 2 diabetes mellitus, as described herein. Lixisenatide is prepared as described herein, in particular as a liquid formulation le for parenteral administration.

Another aspect of the present invention is a method of ric treatment, said method comprising administering to a patient in need of a pediatric treatment, a pharmaceutical combination, said combination comprising (a) lixisenatide or/and a pharmaceutically able salt f, and (b) metformin or/and a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is a method of pediatric treatment, said method comprising administering to a patient in need of a pediatric treatment, a pharmaceutical combination, said combination comprising (a) natide or/and a pharmaceutically acceptable salt thereof, and (b) a basal n or/and a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is a method of pediatric treatment, said method comprising administering to a patient in need of a pediatric treatment, a pharmaceutical combination, said combination comprising (a) lixisenatide or/and a pharmaceutically acceptable salt thereof (b) metformin or/and a pharmaceutically acceptable salt thereof, and (c) a basal insulin or/and a pharmaceutically acceptable salt f. in these methods of treatment, the pediatric patient is a patient as described herein. in particular, the pediatric patient suffers from type 2 diabetes mellitus, as described herein. Lixisenatide is prepared as described herein, in particular as a liquid formulation suitable for parenteral stration.

Metformin is prepared as bed herein, in particular for oral administration. The basal insulin is prepared as described herein, in particular as a liquid formulation suitable for parenteral administration.

Yet another aspect of the t invention is a method for the improvement of glucose excursion, for the improvement of the postprandial plasma glucose concentration, or/and for the improvement of plasma glucagon concentration, said method comprising administering to a pediatric patient, as described herein, (i) lixisenatide or/and a pharmaceutically able salt thereof, or (ii) the combination as described herein.

Yet another aspect of the present invention is the use of lixisenatide or/and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in pediatrics (for pediatric treatment). The pediatric patient is a patient as described herein. in particular, the medicament is for the treatment of type 2 diabetes mellitus, as described herein. Lixisenatide is prepared as bed herein, in ular as a liquid formulation suitable for parenteral administration.

Yet another aspect of the present ion is the use of a pharmaceutical combination, said combination comprising (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, and (b) metformin or/and a pharmaceutically acceptable salt thereof, for the manufacture of a ment for use in pediatrics (for pediatric treatment).

Yet another aspect of the present invention is the use of a pharmaceutical combination, said ation sing (a) lixisenatide or/and a pharmaceutically acceptable salt f, and (b) a basal insulin or/and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in pediatrics (for pediatric treatment).

Yet another aspect of the present invention is the use of a pharmaceutical combination, said combination comprising (a) lixisenatide or/and a pharmaceutically acceptable salt thereof, (b) metformin or/and a pharmaceutically acceptable salt f, and (c) a basal insulin or/and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in pediatrics (for pediatric treatment).

In these uses, the pediatric patient is a patient as described herein. In particular, the medicament is for the treatment of type 2 diabetes mellitus, as described herein.

Lixisenatide is prepared as bed herein, in particular as a liquid formulation suitable for parenteral administration. min is prepared as described herein, in particularfor oral administration. The basal insulin is prepared as described herein, in ular as a liquid formulation suitable for parenteral administration.

Yet r aspect of the t invention is the use of (i) Iixisenatide or/and a pharmaceutically acceptable salt thereof, or (ii) the combination as described herein, for the manufacture of a medicament for the improvement of glucose ion, for the improvement of the postprandial plasma glucose concentration, or/and for the improvement of plasma glucagon concentration, wherein the patient to be treated is a pediatric patient, as described herein.

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

Figure legends Figure 1 Graphical study design of Example 1. * Mandatory blood sampling D—30 to 0—25 for laboratory tests (eg, anti—lA2 and anti—GAD autoantibodies, fasting C—peptide). The following assessments will be done at TPl, TP2, TP3 and E08: Physical ation and vital signs, ECG and AE assessment (except ing).

Figure 2 3 cartridges for injections Figure 3 Body mass index (BMI) for age percentiles by gender: Boys, 2 to 20 years RECTIFIED SHEET (RULE 91) ISA/EP Figure 4 Body mass index (BMI) for age percentiles by gender: Girls, 2 to 20 years Figure 5 Mean i SEM plasma glucose per ent group in adult ts - evaluable PD population Figure6 Mean i SEM plasma glucose per treatment group in pediatric patients — evaluable PD population Figure? Median plasma glucose (mmol/L) per treatment group in adult patients - evaluable PD population RECTIFIED SHEET (RULE 91) ISA/EP Figure 8 Median plasma glucose (mmol/L) per treatment group in pediatric ts - evaluable PD population Figure 9 Median glucagon (ng/L) per treatment group in adult patients - evaluable PD population Figure 10 Median glucagon (ng/L) per treatment group in pediatric patients - evaluable PD population Figure 11 Median plasma insulin (pmol/L) per treatment group in adult patients - evaluable PD population Figure 12 Median plasma n (pmol/L) per treatment group in pediatric patients - evaluable PD population Figure 13 Median C-peptide L) per treatment group in adult ts - evaluable PD population Figure 14 Median C—peptide (nmol/L) per treatment group in pediatric patients - evaluable PD population Figure 15 Mean (+ SD) lixisenatide plasma concentrations by treatment (full PK population, linear scale) Figure 16 Mean (+SD) lixisenatide plasma concentrations by treatment (evaluable PK'population, linear scale) Figure 17 cal study design of Example 3. * o solution and volume to be injected matching to lixisenatide solution: 50 pl during Weeks 1 and 2 (injector device Tactipen®), 200 pl during Weeks 3 and 4 (green injector device Delta14®) and 200 u_ during Weeks 5 and 6 (purple injector device Delta14®) RECTIFIED SHEET (RULE 91) ISA/EP t-matter of the present application is described in the following items: 1. Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use in pediatrics.

RECTIFIED SHEET (RULE 91) ISA/EP ixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to item 1, n lixisenatide or/and the pharmaceutically acceptable salt f is administered as an add-on y to metformin or/and a pharmaceutically acceptable salt thereof.

Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to item 2, wherein metformin or/and the pharmaceutically acceptable salt thereof is prepared for oral administration.

Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein the patient in need of the pediatric treatment has an age of at least 10 years. natide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the ing items, n the patient in need of the pediatric treatment has an age of less than 18.

Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein the patient in need of the pediatric treatment suffers from type 2 diabetes mellitus. _ixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to item 6, wherein the type 2 diabetes mellitus has been diagnosed at least three months before onset of therapy. jixisenatide or/and a pharmaceutically acceptable salt thereof, for use ing to item 6 or 7, wherein the type 2 diabetes mellitus is not adequately lled by metformin monotherapy, by basal insulin monotherapy or by a combination of metformin and a basal insulin. _ixisenatide or/and a pharmaceutically able salt thereof, for use according to any one of the preceding items, wherein the patient in deed of the pediatric treatment is obese. . _ixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein the patient in need of the pediatric treatment has a body mass index of at least 30 kg/m2 or at least 31 kg/mz. 11. Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein lixisenatide is administered about 30 min before breakfast. 12. Lixisenatide or/and a ceutically acceptable salt thereof, for use according to any one of the preceding items, wherein at the onset of treatment with lixisenatide or/and the pharmaceutically acceptable salt thereof, the t has a fasting plasma glucose concentration of at least 8 mmol/L or at least 8.5 mmol/L. 13. Lixisenatide or/and a pharmaceutically able salt thereof, for use according to any one of the preceding items, wherein at the onset of treatment with lixisenatide or/and the pharmaceutically able salt thereof, the patient has a 2 hours postprandial plasma glucose concentration of at least 11.1 mmol/L or at least 12 mmol/L. 14. Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use ing to any one of the preceding items, wherein at the onset of treatment with lixisenatide or/and the ceutically acceptable salt thereof, the patient has a glucose excursion of at least 3 mmol/_, n the e excursion is the difference of the 2 hours postprandial plasma glucose concentration and plasma glucose concentration 30 minutes prior to a meal test. . _ixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein at the onset of treatment with lixisenatide or/and the pharmaceutically acceptable salt thereof, the patient has a HbA1c value of at least about 7 %, at least about 7.5 %, at least about 8 %, at least about 8.5 %, at least about 8.65 %, or at least about 9 %. 16. natide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein at the onset of treatment with lixisenatide or/and the pharmaceutically acceptable salt thereof, the patient has a plasma glucagon level of at least 140 ng/L. 17. Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, n at the onset of treatment with lixisenatide or/and the pharmaceutically acceptable salt thereof, the patient has a ide plasma concentration of at least 1.2 nmol/L. 18. Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein lixisenatide or/and the pharmaceutically acceptable salt thereof is prepared for parenteral administration. 19. Lixisenatide or/and a pharmaceutically acceptable salt thereof, for use according to any one of the preceding items, wherein lixisenatide is administered in a daily dose selected from the range of 5 pg to 10 pg.

.Lixisenatide or/and a pharmaceutically acceptable salt thereof ing to any one of the preceding items, for use in the improvement of glucose excursion, for use in the improvement of the postprandial plasma glucose concentration, or/and for use in the improvement of plasma glucagon concentration. 21.A pharmaceutical combination for use in pediatrics, said combination comprising (a) natide or/and a pharmaceutically acceptable salt thereof, and (b) metformin or/and a ceutically acceptable salt thereof. 22.The pharmaceutical combination for use ing to item 21, wherein lixisenatide or/and the pharmaceutically acceptable salt f is ed for parenteral administration. 23.The ceutical combination for use according to item 21 or 22, wherein metformin or/and the pharmaceutically able salt thereof is prepared for oral administration. 24.The pharmaceutical ation for use according to any one of the item 21 to 23, wherein the patient in need of the pediatric treatment suffers from type 2 diabetes mellitus.

.The pharmaceutical combination according to any one of the item 21 to 24, for use in the improvement of glucose excursion, for use in the improvement of the postprandial plasma glucose concentration, or/and for use in the ement of plasma glucagon concentration. 26A method of pediatric treatment, said method comprising administering to a patient in need of a pediatric treatment, lixisenatide or/and a pharmaceutically acceptable salt thereof. 27.The method according to item 26, wherein natide or/and the pharmaceutically acceptable salt thereof is prepared for parenteral administration. 28.The method according to item 26 or 27, further sing administering metformin or/and a ceutically acceptable salt thereof to the patient. 29.The method according to item 28, wherein metformin or/and the pharmaceutically acceptable salt thereof is prepared for oral administration.

.The method according to any one of the items 26 to 29, wherein the patient in need of a pediatric treatment suffers from type 2 diabetes mellitus. 31.Use of natide or/and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in pediatrics.

Example 1 A randomized, double-blind, placebo controlled trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of lixisenatide in paediatric (10 — 17 years old) and adult patients with type 2 es A randomized, double-blind, placebo controlled trial to assess safety, tolerability, cokinetics and codynamics of lixisenatide in paediatric (10 - 17 years old) and adult patients with type 2 diabetes. lNVESTlGATOR/TRIAL LOCATION Multi—center STUDY 0 BJ ECTIVE(S) Primary objective: c To investigate the effects of a single subcutaneous lixisenatide dose of 5 pg and 10 pg as compared to placebo in reducing postprandial e (PPG) assessed as area under the plasma glucose concentration curve (AUC) after a standardized liquid meal (breakfast) in type 2 diabetic paediatric population (10—17 years old) and adults as controls ary objectives: To evaluate in both paediatric and adult populations: . pharmacokinetic parameters of lixisenatide in plasma after single subcutaneous ascending doses 0 the maximum PPG excursion, and on the changes in insulin, C—peptide and glucagon plasma concentrations following a standardized breakfast safety and tolerability Phase I, multicenter, double—blind, randomized, placebo controlled, single—dose, 3—period, 3-treatment, 6 sequence cross- over study in paediatric and adult with type 2 diabetic patients (see Section 6.1 ) The study is double blind with regard to active treatment versus placebo. The study drug volume (i.e., dose of active drug at 5 pg and 10 pg or matching o) is not blinded but placebo, volumes matched to 5 pg and 10 pg in a ratio 1:1.

STUDY POPULATION Inclusion criteria: Main ion criteria: 0 Male and female patients with type 2 diabetes mellitus (T2DM), as defined by WHO (fasting plasma glucose 27 mmol/l (126 mg/dl) or 2 hours postprandial plasma glucose 211.1 mmol/l (200 ), diagnosed at least 3 months at the time of screening visit, with or without min (stable dose for at least 4 weeks prior to randomization) o HbA1c 2 7% and S 10% at screening o g C-peptide at screening > 0.6 ng/mL a ve test for anti-islet cell antibodies (or insulinoma associated protein (IA2)) and anti-glutamic acid decarboxylase (GAD) autoantibodies Paediatric population: o Male and female 2 10 and < 18 years of age with at least 3 patients below 15 years of age and limited to 3 patients 2 16 years of age, BMI > 85th percentile for age and gender (body weight > 50 kg) Adult population: 0 Male and female patients a 18 and S 65 years of age and with BMI > 25 kg/m2 and S 37 kg/m2 ion criteria: 0 Diabetes other than T2DM 0 Use of antihyperglycaemic nal product(s), other than metformin . History of unexplained pancreatitis 0 Personal or family history of ary thyroid cancer (MTC) or genetic ions that predispose to MTC (eg, multiple endocrine neoplasia syndromes) 0 Calcitonin 2 20pg/mL (5.9 pmol/L)at screening Total expected number of patients: 12 paediatric patients and 12 adult patients with type 2 diabetic patients lNVESTIGATOR/TRIAL LOCATION Worldwide STUDY TREATMENT(s) Compound Dose Form Route of nvestigational Medicinal Product(s) administration Cormulation: natide 5 ug in solution for aneous 50 pL injection injection 100 ug/mL Lixisenatide 10 ug in solution for subcutaneous 100 uL injection injection 100 ug/mL Lixisenatide is supplied as a sterile aqueous solution for subcutaneous (5.0.) ion in a 3-mL glass cartridge.

Placebo is supplied as 3—mL aqueous solution (in cartridge).

Both to be ed with the OptiClik® self—injector device.

Route(s) of administration: Thin needles will be used to minimize discomfort.

Dose regimen: 3 treatment periods each lasting 2 days. In each ent period patients receive a subcutaneously injected single dose of either 5 ug or 10 pg lixisenatide with 5 ug preceding the 10 pg dose level or volume matched placebo (50 uL or 100 ML).

IMP will be administered in fasted conditions 30 min before a standardized, liquid meal (breakfast).

Non lnvestigational Medicinal Product(s) NA RIMARY ENDPOINT(S) AND MAIN codynamics: ECONDARY ENDPOINT(S) primary endpoint: a Plasma glucose: GLU-AUCO:30-4:30h2 area under the curve for plasma glucose concentration time profile calculated from time of rdized breakfast start (30 min after IMP injection=T0.5 until 4 hours later T4.5 subtracting the pre- meal value T0.5h Secondary nts: 0 Post Prandial Glucose excursion (PPG0230—430h): maximum change from time of standardized breakfast start (30 min after IMP injection=TO.5) until 4 hour later (T45) in postprandial plasma glucose o Insulin, ide and glucagon (AUCOflMflOh) : area under the curve for insulin, C-peptide and on concentrations time profiles from time of standardized breakfast start (30 min after lMP injection=TO.5) until 4 hours later (T45) o Pharmacokinetics: lixisenatide plasma concentration, PK parameters (Cmax, Tmax, t, AUG) 0 : clinical laboratory, ECG parameters, vital signs, local tolerability and e events ASSESSMENT SC Pharmacodynamics: Blood samples will be taken immediately prior to IMP injection min before a standardized breakfast, then just prior to the standardized breakfast, and at 30, 60, 90, 120, 180, and 240 min thereon for glucose assessments on Day 10f each of the 3 treatment periods for GLU-AUCosmsm.

For secondary endpoints including safety refer to study and period flow charts.

STATISTICAL CONSIDERATIONS Both overs will be ed separately. Results will be compared between the two populations descriptively.

Pharmacodynamics: Analysis of population: The pharmacodynamic population will consist of patients randomized and d and having blood samples for reliable evaluation.

Within each cross—over, the analyses of the primary pharmacodynamic nt will be performed based on the pharmacodynamic population. GIU—AUCO:30-4:30h will be analyzed using a linear mixed model with sequence, period, and treatment effect and patient-within-sequence as random effect, and the T05 h plasma e concentration as covariate. The least square mean differences between treatment groups and the corresponding 90% confidence interval (CI) will be calculated within the linear mixed model framework. A significance level of p< 0.05 will be used.

Secondary codynamic parameters will be analyzed using the same statistical model as described above with the corresponding T0.5 h values as covariates.

Pharmacokinetics: Log- transformed lixisenatide pharmacokinetic parameters Cmax, AUClast, and AUC will be analyzed using a linear mixed effect model with fixed terms for sequence, ‘ treatment and a random term for a patient-within-sequence. Estimates and 90% CI for the geometric mean ratio of 5 pg lixisenatide and versus lopg lixisenatide will be obtained by computing estimate and 90% CI for the difference between treatment means within the linear mixed effects model framework, and then converting to ratio by the antilog transformation to the original scale.

Safety: The safety analysis will be based on the review of the individual values (clinically significant alities) and descriptive statistics (summary tables and plots if appropriate) by treatment.

Treatment-emergent adverse events ) classified in system-organ classes and preferred terms then summarized by number and percentage of patients and number of TEAEs.

Individual clinical laboratory data, vital sign. and ECG data will be listed and flagged for potentially ally significant abnor- malities (PCSAs) and for lower and upper clinical laboratory limits. Frequency of patients with alities and with PCSAs will be summarized for each type of parameter by treatment.

DURATION OF STUDY PERIOD Screening: D -30 to D -2 prior to inclusion with a minimal period (per patient) of 25 days ent Period: 3 Periods each lasting 1 day (up to 2 days if there is an institutionalization on 0-1 evening ) (discharge in the oon of Di of each period) E08: 1 to 6 days after last dosing (DZ to 07 after Period 3) Total duration: 4 to 7 weeks 1. FLOW CHARTS 1.1 GRAPHICAL STUDY DESIGN The graphical study design of Example 1 is shown in Figure 1.

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AB: Adverse event ARAC: Allergic Reaction Assessment Committee ARAC: ic Reaction ment Committee BMI: Body mass index CRF: Case Report Form CV: cardiovascular ECG: , Electrocardiogram FSH: Follicle— stimulating hormone GAD: Glutamic acid decarboxylase GLP—l; Glucagon—like e— 1 1A2: Insulinoma ated protein IMP: Investigational Medicinal Product lXRS: Interactive Voice and Web Response System MTC: Medullary thyroid cancer PPG: Postprandal glucose SD: standard deviation SEM: standard error of the mean SU: Sulfonylurea TZDM: Type 2 diabetes mellitus 4 INTRODUCTION AND RATIONAL IIII 4.1 INTRODUCTION Lixisenatide is an exendin analog with tic activity on on~like peptide—1(GLP—1) or. The principal eutic potential of lixisenatide to lower blood glucose in T2DM patients has been established in clinical studies. Sanofi—aventis is ting global registration submissions including a Marketing Authorization Application (lVIAA) sion by Centralized Procedure. in the European Union. A total of 42 clinical studies were conducted or are ongoing, ing 24 Phase 1 studies, 5 Phase 2 studies and 13 Phase 3 studies.

A large Phase 3 program (the “GetGoal” clinical trial m) ted throughout 48 countries and approximately 900 sites have been initiated to assess the safety and cy of lixisenatide. The l program has enrolled more than 4500 adult patients with T2DM (more than 2700 of them receiving lixisenatide). This program includes 10 studies with a duration ranging fiom 12 to more than 76 weeks. In addition to the GetGoal program, one Phase 3b study has been completed and a second Phase 3b study and a large placebo—controlled study to evaluate cardiovascular outcomes during treatment with lixisenatide are ongoing.

In the phase 3 studies that have been completed and ed so far [AVEOOlO Clinical Investigator’s rochure, latest version]: o The y of lixisenatide on glycemic control was confirmed o Lixisenatide was safe and well tolerated: - As expected for a GLP—1 receptor agonist the most frequent adverse events were gastrointestinal in nature, mainly nausea, with low rates of vomiting and diarrhea.

Most of these events were transient, mild to moderate in intensity and resolved spontaneously without sequelae.

— Reported ycemia events were mostly mild to moderate in intensity. The incidence was similar to placebo when lixisenatide was used in monotherapy. In the EFC10887 study, in which 70% of the patients were receiving a background ent with basal insulin in combination with a sulfonylurea (SU), the percentage of patients with symptomatic hypoglycemia was higher with lixisenatide (42.9%) versus placebo (23.6%). r, in the. subgroup of patients not treated with a SU, the incidence of patients with symptomatic hypoglycemia was similar in the placebo and lixisenatide groups (32.6% with lixisenatide and 28.3% with placebo).

- In a comparative study versus exenatide (10 ug twice daily), significantly fewer patients treated with lixisenatide 20 ug once daily experienced symptomatic hypoglycemia events (5.0% in the lixisenatide arm vs 14.6% in the exenatide arm).

Lixisenatide also offered better gastrointestinal tolerability with fewer patients experiencing nausea or vomiting.

There have been no paediatric clinical trials conducted as of today with lixisenatide.

More detailed information is provided in the Clinical lnvestigator’s Brochure (1). 4.2 RATIONALE 4.2.1 Study rationale Until recently, TZDM was almost exclusively an adult disease. ding with the sing prevalence of y in children, the incidence of TZDM in children and cents has markedly increased to the point that it accounts for as many as one third of all the new cases of TZDM diagnosed in adolescent. en/adolescents with TZDM are usually diagnosed over the age of 10 years, in middle to late puberty, when due to physiological changes in the GH/IGF—l axis insulin ance develops.

Like in adults, the incidence of type 2 diabetes in children/adolescents-is highest in some ethnic populations (e, g. American Indians, African American, Asian/pacific Islander and Hispanics) (2).

Diabetes is a therapeutic area for which the aEMA Paediatric Working Party considers that research and development of medicinal ts for en should be performed. Type 2 diabetes may have an earlier and more aggressive course in paediatric patients; therefore, they are likely to be at higher risk for ping complications and need the best possible glycemic control in the early stage of their disease.

As of today, mettOrmrn is commonly ed as the first pharmacotherapy in managing TZDM in children above 10 years and in adolescent in addition to diet and exercise (5, 6, 7). This drug has indeed shown to be safe and effective in randomized controlled trials d out in this population (8) Nevertheless, in many patients, progression is rapid, and control of hyperglycaemia may become insufficient even at maximal tolerated doses of metformin.

Therefore, we propose to evaluate pharmacokinetics, pharmacodynamics and safety / efficacy of lixisenatide in a paediatn'c population. 4.2.2 Population to be studied The population to be studied comprises patients with diabetes mellitus type 2 on diet and exercise, With or Without a stabletreatment of metformin, with an age of 10 to 17 years for the paediatric populationhand 18 to 65 years for the adult population. BMI will be either > 25 kg/m2 (adults) or BMI > 85 tile for age and gender (paediatric population). 4.2.3 Design rationale and risk assessment The cross—over, blinded and randomized design allows enhancing the ivity to assess true effects by analyzing for differences between lixisenatide and placebo within each participant, while avoiding influence of between patient variability.

Subjects with diabetes mellitus type 2 with a background metformin therapy (with stable dose :2 10 % for at least 4 weeks prior to randomization) can be included and their metformin therapy will not be changed throughout the study. As insulin releasing treatments (e. g. sulfonylureas) require long wash out periods, subjects on insulin agogues will not be asked to participate.

A dose of 10 ug results in mean peak plasma concentrations of about 50 pg/mL about 2 hours after injection (1).

In a phase I study, single doses of 1ixisenatide from 3 ug lower PPG in TZDM patients but at least ug lixisenatide caused a clear ation of the rise in plasma glucose induced by a standardized liquid meal stered 1 hour after dosing (Study AV 4 0010A/01—016, see details in the Clinical Investigator’s brochure (1)).

The elimination half life for 1iXisenatide administered to adult TZDM patients is around 3 to 4 hours. The quick disappearance of lixisenatide from the circulation when absorption is te enables short wash—out periods of 1 day. As a consequence the end—of—study visit can occur within a week.

Lixisenatide has been studied in subjects with type 2 diabetes mellitus, and has a record of safety and bility which allow further single dose ments. The most common e effects upon single dose administration in patients with type 2 diabetes mellitus were headache, nausea, and injection site reactions. As GLP—1 mediated insulin release is depending on plasma glucose concentration, and decreases to absence with lower glucose concentration, the risk for hypoglycemia is very limited.

Hospitalization and close supervision of participants by professional staff members in the research unit on Day 1 ensure maximum protection against uences of unforeseen adverse . 4.2.4 Dose, Regimen, and Treatment on Rationale The maximum dose evaluated in the g phase 111 program is 20 pg QD with a preceding starting dose of 10 ug. In this planned study (PKD11475) the dose of 5 ug corresponds to 50 % of the starting dose in adults. Randomization will assure that in any patient the first lixisenatide treatment will be at a dose level of 5 ug.

Since pharmacodynamic effects of lixisenatide such as lowering ofPPG after a test meal could be demonstrated even after the very first dose, a single—dose study is considered appropriate to compare pharmacodynamic effects between adult and paediatric populations. 4.2.5 Specific parameters rationale 1 Postprandial plasma glucose after a standardized breakfast natide is known to exert glucoregulatory effects, including enhancement of glucose~ dependent insulin secretion, reduction of glucagon secretion, reduction of food intake, and slowing of gastric emptying. After a meal, the gastrointestinal tract regulates the rate at which carbohydrate and nutrients are absorbed and it is known to release regulatory peptides that ate insulin secretion fiom pancreas. Although the rate of c emptying does not affect insulin secretion directly, it regulates the delivery of nts to the small intestine and, therefore, has a major impact on the, timing and ude of the blood e excursion, thereby modulating insulin secretion indirectly.

Therefore, beside the assessment of postprandial plasma glucose (primary endpoint) after a standardized meal, study ives include the evaluation of the effects of lixisenatide on secretion of insulin, glucagon and C—peptide. 4.2.5.2 Specific safety parameters Amylase and lipase: Because some cases of acute pancreatitis have been reported with marketed GLP—l agonists (7), patients with amylase and lipase above 3 times the upper limit of normal at screening will be excluded from the study, and amylase and lipase will be monitored.

STUDY OBJECTIVES .1 PRIMARY 0 To investigate the effects of a single subcutaneous lixisenatide dose of 5 ug and 10 ng as compared to o in reducing postprandial glucose (PPG) assessed as area under the plasma glucose concentration curve (AUC) after a standardized liquid meal (breakfast) in type 2 diabetic paediatric population (10-17 years old) and adults as controls. .2 SECONDARY To te in both paediatric and adult populations: 0 Pharmacokinetic parameters of lixisenatide in plasma after single subcutaneous ascending doses 0 The maximum PPG ion, and on the changes in insulin, sulin, C—peptide and glucagon plasma concentrations following a standardized breakfast 0 Safety and tolerability. 6 STUDY DESIGN 6.1 DESCRIP“ION OF THE PROTOCOL Graphical study design/flow charts — please refer to flow charts in Section 1.

This is a phase I, multicenter, double-blind, randomized, placebo controlled, single-dose, 3~ , 3—treatment, 6 sequence cross-over study in paediatric and adult with type 2 diabetic patients.

The study is double blind with regard to active treatment versus placebo. The study drug volume (i.e., dose of active drug at 5 pg and 10 pg or matching placebo) is not blinded.

There are 3 treatment periods l~7 days apart, each period lasting only one day (Day 1) with an early start in the morning up to the beginning of the afternoon. However, ing to the possibilities of the igational site and at the ience of patient, the period may start on ay —1 (afternoon/evening) for all examinations and tests to be done before the IMP administration and before the standardized breakfast (liquid meal). After the dinner on Day—1, patients should stay in fasted conditions for at least 8 hours (food and drink are not allowed except water) up to the standardized breakfast test meal.

In each treatment period, the patients Will receive a subcutaneously injected single dose of either 5 pg or 10 pg natide With 5 pg preceding the 10 pg dose level or volume matched placebo (50 pL or 100 pL) before a standardized test meal.

There are 6 sequences with 3 treatment s, lixisenatide 5 pg, lixisenatide 10 pg, placebo— controlled group (volume of 50 pL or 100 pL) as described in Table l Table 1 - ization schedule per study population (children/adults) Sequence Number Period 1 Period 2 Period 3 of Treatment Treatment ent patients 1 2 o (100 pL) Le. 10 Units* 2 2 Placebo (50 lJL) i.e. 5 Units* 3 2 Placebo (50 lJL) i.e. 5 Units* 4 2 Placebo (100 pL) i.e. 10 Units* 2 Placebo (50 IJL) La 5 Units* 6 2 o (100 pL) Le. 10 Units* * Number of Units indicated in the Opticlick® device 6.1.1 Screening period Overall, the screening period can start on Day —30 up Day —2 before the start of the treatment period. However, laboratory blood sampling must be performed from Day ~30 to Day —25 to get . the results (ie, A and anti—1A2 antibodies) before Day 1.

Patients with type 2 diabetes are screened firstly from Day —30 up to Day -2 (screening phase) and those meeting all inclusion criteria are candidates for a final selection on Day 1 (or Day —1) at the study site (inclusion phase). Patients to be enrolled in this study are patients with type 2 diabetes diagnosed at least 1 year for adults and at least 3 months for paediatric population before the time of screening visit, and patients who are not treated with antihyperglycaemic medicinal product other than metformin with a stable dose(:t10%)'for at least 4 weeks prior to randomization (Day 1) (see Section 7.2).

The first measurements of HbAlc, plasma glucose and C—peptide must be obtained for checking the inclusion criteria of the patients.

Patients meeting all the inclusion criteria and presenting no exclusion criteria are le for the treatment period starting on Day 1. 6.1.2 Treatment period At the convenience of ts and according to the ilities of the igational centre, patient may be institutionalized in the afternoon or evening on Day —l up to the beginning of the oon on Day 1.

After the dinner on Day—1 of each treatment period, patients must fast for at least 8 hours (food and drink are not allowed except water) prior to the IMP administration on Day 1 of each ent period.

On Day 1 of the treatment period 1, patient will undergo the final inclusion examinations and ne safety assessments will be evaluated prior to the first D/IP administration and before the standardized breakfast test meal.

On Day 10f each Period 1, patients will be randomly assigned to one of the six treatment sequences consisting of a od cross—over, separated by washout periods of at least one day up to 7 days n each period (see details Section 6.1.1).

An ‘ dent Person’ will be ed at the investigational centre solely for the administration of NIP, to prevent un-blinding of the clinical team during the conduct of the study. However, activities which are not prone to any bias should be allowed, e.g. data entry of forms filled in by the clinical team, checking position of ECG electrodes etc.

One single SC dose of the following treatment will be administered at each period of treatment 0 One 5 ug dose of liXisenatide (50 uL, 5 Units indicated on the Opticlick®) 0 One 10 ug dose of lixisenatide (100 uL, 10 Units indicated on the Opticlick®) o 50 uL placebo solution (5 Units indicated on the Opticlick®) or 100 uL placebo solution (10 Units indicated on the Opticlick®) At each treatment period, patients will undergo an 8—point plasma glucose profile, a 7—point profile of insulin, C—peptide and glucagon, and a 8—point pharmacokinetic profile up to 6.5h after the MP administration as well as safety assessments before leaving the CR0 or investigational centre. ‘ 6.1.3 —study visit The end of study visit should be scheduled on 32 to D7 of the Period 3.

Concerning the procedure to be followed in case of premature permanent discontinuation of treatment with investigational product, please refer to Section 11 . 6.2 DURATION OF STUDY PARTICIPATION 6.2.1 Duration of study participation for each patient 0 Screening duration: 25 (blood sampling for autoantibodies testing) to 30 days 0 3 ent period(s): only 1 day (1 treatment day) to 2 days (if patient will arrive on Day -1) each a Wash—out period between each period: at least 1 day up to 7 days 0 End of study: 1 to 6 days after last dosing (D2 to D7 after Period 3) a Total study duration from screening per t: 4 to 7 weeks at maximum However, patient ipation could be prolonged in case of safety concerns (see n10.3.3.l). 6.2.2 Determination of end of cIinicaI triaI (all patients) The end of the clinical trial is defined as the day the last patient completed his/her last visit planned in the protocol. 6.3 STUDY COMMITTEES 6.3.1 Allergic Reaction Assessment Committee Since lixisenatide is a peptide that may potentially generate allergic reactions, an Allergic Reaction Assessment Committee (ARAC) has been setup. The ARAC is a committee of experts in the field of allergy, independent from the Sponsor and the igators, implemented to assess allergic reactions or allergic—like reactions that may occur during the study. The mission of the ARAC is to adjudicate, in a timely manner, all allergic, or possible allergic events. The ARAC is blinded regarding the study treatment. mes transient, injection site reactions, irritant in nature may occur, requiring no intervention and being of dubious significance. These ons would not be considered to be allergic reactions.

Virtually all symptoms listed on the CR 4‘ “Allergic Reaction Complementary Form” are possible adverse reactions that may be allergic in nature and may need to be addressed after medical nt, excluding another etiology than allergy. e events that may cOnstitute an allergic reaction (e.g., generalized itch, nasal itch, swelling at injection site, flushing, hives, swelling at lips, eyes, face, tongue, hands, feet, lump in throat, difficulty to w, hoarseness, change in pitch of voice, incapacity to speak, ng, chest tightness, stridor, etc) should be considered to be reported on the Allergic Reaction Complementary Form.

Adverse events that are obviously not of allergic origin (e. g., local injection site reactions) should not be ed on the Allergic Reaction Complementary Form.

The ARAC reviews the reported cases and determines the nature of the events, confirms the allergic nature or alternative diagnosis based on the information reported by the igator. A detailed charter describes the ARAC procedures. 7 SELECTION OF PATIENTS 7.1 NUMBER OF PATIENTS PLANNED Twelve (12) paediatric patients and 12 adult diabetic patients are to be enrolled for final Pharmacodynamics evaluation. 7.2 INCLUSION CRITERIA Patients meeting all of the following criteria will be considered for enrollment into the study: Demography 101. Age eligibility for tric population: 2 10 years and <18 years with at least 3 patients below 15 years and no more than 3 patients aged between 16 and 18 years (see below in Table 2) Table 2 — Subset definition for paediatric population Age range ) Number of paediatric patients (n=12) Age range 2 10 3 to 10 and <15 Age range 2 15 l to 8 and < 16 Age range 2 16 l to 3 and <18 Age eligibility for adults: 2 18 and S 65 years.

I 02. BMI > 85th percentile for age and gender in children, body weight > 50 kg dix A); 1 BMI > 25 kg/m2 and s 37 kg/m2 for adults Health status Male and female patients with type 2 diabetes us, as defined by WHO (fasting plasma glucose 27 mmol/l (126 mg/dl) or 2 hours postprandial plasma glucose 211.1 mmol/I (200 mg/dl)), diagnosed for at least 1 year for adults and at least 3 months for paediatric population at the time of ing visit, with Or without metformin (stable dose i10% for at least 4 weeks prior to randomization) I 04. HbAlc 2 7% and E 10% at screening I 05. Fasting C—peptide at screening > 0.6 ng/mL I 06. ve test for anti—inSulinoma associated protein (1A2) and anti—glutamic acid decarboxylase (GAD) autoantibodies I 07. Menstruating females must have a regnancy (serum beta HCG) test for inclusion (Tanner Stage 2 3) I 08. Women of childbearing potential (including ‘seirualxactivev girls).rnust_use a double ceptive method throughout the study asjudgedby themvestigator, except if she has undergone sterilization at least 3 months prior to the time of screening or is postmenopausal. The accepted double contraception methods include use of a highly effective method of birth control (intrauterine device or hormonal contraception) in addition to one of the following contraceptive options: (1) condom; (2) diaphragm or cervical/vault cap; (3) spermicide (CPMP/ICH/286/95, modification) Note: Menopause is defined as being over 60 years of age, or between 45 and 60 years of age and being amenorrheic for at least 2 years with plasma FSH level > 30 UI/L.

Regulations I 09. Adult patient having given written informed consent prior to undertaking any study-related procedure and for miner’s, provision of Informed Consent Form signed by the t’s parent(s)/legal representative. In addition, provision of Assent Form signed by minor patient or Informed Consent Form signed by emancipated or mature minors (defined by local lows) I 10. Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the al laws in force relating to biomedical research. (to be adapted if needed, country c) I 11. Not under any administrative or legal ision. 7.3 EXCLUSION CRITERIA 7.3.1 Echusion criteria related to study methodoIogy E 01. If female, pregnancy (defined as positive urinary ncy test), breast—feeding E 02. Diabetes other than type 2 diabetes E 03. History of metabolic acidosis, including diabetic idosis within 1 year prior to screening E 04. Hemoglobinopathy or hemolytic anemia E 05. History of dial infarction, stroke, or heart failure requiring hospitalization within 6 months prior to the time of screening, y or ce of clinically significant diabetic retinopathy, history or ce of macular edema likely to require laser treatment within the study period , 06. Cardiovascular, hepatic, neurological, endocrine disease, active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult (euthyroid patients on replacement therapy will be included if the dosage of thyroxin is stable for at least three months prior to screening Visit) E 07. For adults, uncontrolled or inadequately controlled hypertension at the time of screening with a g ic or lic blood pressure > 160 mmHg or > 95 man, respectively 108. For children, abnormal blood pressure levels greater or equal to 90th percentile adjusted for age, gender and height percentile (Appendix B) '3 O9. Positive test for insulinoma associated protein (1A2) and ic acid decarboxylase (G )) autoantibodies E10. Any clinically significant abnormality fied on physical examination, laboratory tests or vital signs at the time of screening that in the judgment of the investigator or any sub investigator would preclude safe completion of the study E11. Receipt ofblood or plasma products within 3 months prior to the time of screening *1 12. igator or any sub investigator, pharmacist, study coordinator, other study staff or relative thereof ly involved in the conduct of the protocol iii 13. Patients considered by the investigator or any sub investigator as inappropriate for this study for any reason (e.g. impossibility to meet specific protocol requirements, such as scheduled visits, being able to do self—inj ections, etc) E14. Use of other oral or injectable antidiabetic or hypoglycemic agents other than metformin (e.g., alpha glucosidase inhibitor, exenatide, DPP—IV inhibitors, insulin etc.) within 3 months prior to the time of screening E 15. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one week or more within 3 months prior to the time of screening .2 16. For children, known allergy to local etics (e. g., Emla® Elamax® cream , , Ethyl Chloride) 417. Likelihood of requiring treatment during the screening phase and treatment phase with drugs not permitted by the clinical study protocol * 18. Use of any investigational drug within 3 months prior to screening 7.3.2 Exclusion criteria related to the current knowledge of iixisenatide and/or metformin Exclusion criteria related to lixisenatide: E 19. Clinically nt y of gastrointestinal disease associated with prolonged nausea and vomiting, including, but not limited to gastroparesis and gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening .LiJ 20. Any previous treatment with lixisenatide E21. Allergic on to any GLP—l st in the past (eg. exenatide, liraglutide) or to metacresol E 22. History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease * 23. Personal or family history of medullary thyroid cancer (MTC) or c conditions that predispose to MTC (e.g., le endocrine neoplasia syndromes) E 24. Known y of drug or alcohol abuse within 6 months prior to the time of screening E 25. Laboratory findings at the time of screening: In adults — ALT > 3 times the upper limit of the normal laboratory range — Total bilirubin: > 1.5 times the upper limit of the normal laboratory range (except in case of Gilbert’s syndrome) — Hemoglobin < 11 g/dL and/or neutrophils < 1,500/mm3 and/or platelets < 100,000/mm3 In paediatrics: — ElevatiOnsin blood tests of renal (serum creatinine > 1.0 mg/dL) and]or liver (ALT, AST and/or bilirubin) >2 times the upper limit of normal (ULN) for age.

— Hemoglobin < 11 g/dL and/or neutrophils < 1,500/mm3 and/or platelets < 100,000/mm3 In /paediatrics: — Calcitonin Z 20 pg/mL — Amylase and/or lipase above 3 times the upper limit — Positive result on any of the following tests: hepatitis B e (HBs Ag) antigen, anti—hepatitis C virus (anti—HCV) antibodies, anti—human immunodeficiency virus 1 and 2 antibodies (anti—HIV 1 and anti HIV2 Ab).

E 26. Positive alcohol test.

Exclusion criteria related to the background therapy (i.e. metformin): E 27. Renal ment in adult defined with creatinine clearance < 60 mL/min using the Cockcroft— Gault Formula (see Appendix C) A patient may not be enrolled in this study more than once (i.e. randomized twice). 8 TREATM ENTS 8.1 DIET AND EXERCISE Lifestyle and diet therapy provided before the time of screening is to be continued during the study in a similar manner. Dietary and lifestyle counseling should be given by a Registered Dietitian or other qualified nutrition professional (eg, diabetic educator, etc) and should be consistent with the recommendations of international or local guidelines (with regard to the distribution of calories among carbohydrates, proteins, and fats, exercises, etc) for type 2 ic patients.

At each of 3 treatment periods, adult and paediatric ts will ingest a standardized meal test, min. after the IMP administration to assess fasting and post—prandial glucose.

For adults and paediatrics, the standardized breakfast meal is a 400 mL drink (Ensure Plus® Drink, Abbott). It contains 600 kcal and is composed of 53.8% carbohydrate, 16.7% protein and 29.5% fat (see details in Appendix D).

The composition and the quantity of the standardized meal must be identical at each treatment period.

The standardized meal for all adult and paediatric ts should be ed within a 15 — minute period. 8.2 INVESTIGATIONAL NAL DRODUCT 8.2.1 Lixisenatidelplacebo o Lixisenatide pharmaceutical form: Sterile aqueous solution for subcutaneous (s.c.) injection in a 3-mL glass cartridge, containing the active ingredient 300 ug (i.e. 100 , ol, sodium acetate trihydrate, methionine, meta—cresol, HCL/NaOH and water for injection. 0 Control drug: matching o, s solution for subcutaneous injection. 0 Route and method of administration: Subcutaneous injection using the pen-type injector (OptiClik®). Lixisenatide injection will be performed in the clinical unit by a person experienced with s.c. Administration will be by deep s.c., alternating n the left and right anterolateral and the left/right posterolateral nal walls. Within a given area, location should be changed (rotated) at each time to prevent injection site skin reaction. 0 Dose of the lixisenatide investigational medicinal product (MP) per administration: Once injection in the morning of Day 1 of each period 0 Timing: lixisenatide will be stered at around 07:30 in the morning in fasted condition (breakfast will be taken 30 minutes after the injection) o For the correct dosing of Lixisenatide and placebo volume, the units of the ik® pen have to be settled as described in Table l. o Lixisenatide IMP will be provided by the sponsor. 8.2.2 Description of the or device OptiClik® A pen—type injector (OptiClik®) with Optifine 8TM (8 mm X31G) needles from Ypsomed are provided to each igational centre for the injection of liXisenatide or its o, specifically labeled for the use of the study (“lixisenatide”) in accordance with applicable regulatory requirements. Handling procedure of the pen-type in]ector and administration technique of natideis providedin a specific manual.

Pen—device or cartridges related issues (malfunctions) should be reported to the sponsor or the Wharehouse by the means of a procedure on product technical complaint (PTC) forms, which is described in a separate manual. 8.2.3 Dosage schedule According to the randomization schedule (Section 6.1) the lixisenatide dose per injection or the placebo volume (Day 1) is to be administered 30 minutes before breakfast and for the correct dosing, the units of the ik® pen will be administered as follows: 0 5 pg lixisenatide = 05 Units indicated on OptiClik® (= 50 uL) o 10 pg liXisenatide = 10 Units indicated on OptiClik® (= 100 11L) 0 50 uL (0.05 mL) placebo = 05 Units ted on OptiClik® o 100 uL (0.10 mL) placebo = 10 Units indicated on OptiClik® 8.3 NONINVESTIGATIONAL M EDICINAL PRODUCTS The possible background therapy (ie, metformin only) is not considered as non investigational medicinal product. 8.4 DESCRIPTION OF BLINDING METHODS The lixisenatide investigational t and o are indistinguishable.

The treatment allocation (on Day 1 of each period) will be -blinded and will be done according to a randomization list. The treatment codes will be generated according to sanofi- aventis procedure.

For blinding purposes the on—site administration of natide or its o will therefore be performed by an independent person who is not a member of the clinical study team at the CRO or investigational site. This “unblinded” person should not be involved in activities which could be biased by the knowledge of the treatment assignment (e.g. A3 assessments, access to pharmacodynamic data). However, activities which are not prone to any bias should be allowed, e. g. blood sampling, vital signs, ECG recording, etc).

OptiClik® pens will be loaded with either lixisenatide or placebo containing cartridges on—site.

Furthermore lixisenatide or its placebo will be administered at different doses resulting also in different volumes. The volume to be injected (see Section 8.2.3) must be set on the ik® pen and is visible to the “unblinded” person responsible for the injection. The “unblinded” person responsible for administration will set the volume to be injected on the OptiClik® pen shortly before injection.

The ARAC members will review and cate allergic ons or allergic-like reactions in a blinded manner. s collected during the lixisenatide treatment periods only will be analyzed for plasma trations. Therefore the bioanalyst(s) at sanofi-aventis responsible for the determination of lixisenatide plasma concentrations will be ded to the randomization code. The results of these assessments will not be ed to the study nel when the study is ongoing except for urgent safety issues. 8.5 METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP At the screening visit, the procedure for assigning of patient number will start only after the provision of the written informed consent by the adult patients to be enrolled or the provision of Informed Consent Form signed by the patient's (s)/lega1 representative of the patient to be enrolled and also the ion of Assent Form or Informed Consent Form signed by the paediatric patient (see inclusion criteria 109).

Then, the investigator or designee has to contact the IXRS and has to e some information to the system (e.g.: date of birth/age of the patient, background oral or inj ectable antidiabetic drugs other than metformin: yes/no, ..). The Interactive Voice and Web Response System (lXRS) will ensure that the enrolment for children Wi11be controlled in respect of the obligations to recruit at least 3 paediatric patients between 10 and 15 years, at least 1 paediatric patient between 15 and 16 years, and no more than 3 paediatric patients above 16 years (inclusion criterion 1 0]).

If criteria are in agreement with the above ent, IXRS will allocate an incremental patient number ing to the chronological order of inclusion. The patient number will be a 9—digit patient number combined of 3 ents Ol—XXX), of which the first 3 digits are the country number (e.g.: for Germany: 276; Mexico: 484; South Africa: 710; UK: 826; US site: 840) the middle 3 digits are the site number (starting with 001) and the last 3 digits are the patient incremental number within the site. The patient number remains unchanged during the study and allows the patient to be identified during the whole study.

On Day 1 of Period 1, the investigator or the designee will contact lXRS and has to provide the following information to the system: patient number, age, and negative test for anti—GAD and anti—1A2 antibodies: . If the patient complies with all inclusion/exclusion criteria, this patient will be considered as randomized. A randomized patient is defined as a patient who is registered, who complies with all inclusion/exclusion criteria and assigned to his /her treatment kit number.

The randomization treatment kit number list is ted centrally by sanofi. The randomization list will be provided by sanofr to the IXRS vendor. The allocation of the treatment kit number to the patients will be performed by IXRS. Patients will e 1MP according to their randomization treatment kit number.

The randomization ratio will be 1:1 for the 2 lixisenatide dose levels (5 pg and 10 pg) and 1:1 for the placebo volumes (50 pL and 100 pL) and 2:1 for each lixisenatide dose versus each placebo volume.

The administration order of the 3 study drugs (5 pg lixisenatide, 10 pg natide, 100 pL placebo or 50 pL placebo) as defined by the randomization plan is defined using the centralized treatment allocation system (IXRS) on Day 1 of the first period after the safety assessments prior to the first IMP ion. The “independent person” (see Section 6.1.2), will administer the first study treatment on Day 1 at each study period in the respect of the written information received by IXRS. The CRO or the investigational site will call IXRS at the end of the last .

Potential replacement patients will have a different identification number (ie, 500 + the number of replaced patients). Each patient will receive the same treatment sequence (the same order of the treatment as the withdrawn patient.

Notes: The randomization of a patient should occur as close as possible to the first administration ofthe IMP. Baseline parameters will be the parameters available the closest before the randomization. 8.6 PACKAGING AND LABELING Cartridges (ie, disposable part of OptiClik®) will be used once at each ent period and are packaged in multiple treatment boxes. Each Box per patient will contain 3 cartridges for injections (1 cartridge to be used per ent period for a single administration).

A ent box containing three cartridges is shown in Figure 2.

Dispensation scheme is described in the study flow chart (please refer to Section 1.3 and n 1.4 ) RECTIFIED SHEET (RULE 91) ISA/EP The content of the ng is in accordance with the local regulatory specifications and requirements. 8.7 STORAGE CONDITIONS AND SHEL‘: LIFE All study drug boxes will be stored in an appropriate safe and locked room under the sibility of the Investigator or other authorized persons (e.g., pharmacists), and must be accessible only to authorized personnel.

Prior to the first use, the investigational products (cartridges) have to be stored between +2°C and +8°C (between 36°F and 46°F), protected from light, and must not be frozen.

When used, the cartridges should be kept. At each treatment period on Day 1, a new cartridge should be replaced. One OptiClik® pen per patient will be used for the 3 single injections. 8.8 RANDOMIZATION CODE BREAKING DURING IH- SIUDY Please refer to Section 9.5.

In case of an adverse event (AS), the code will not be broken except in the stances when knowledge of the IMP is essential for treating the t. prossible, a contact should be initiated with the Sponsor’s monitoring team or medical expert before breaking the code.

No code-breaking material is provided to the igators. For each patient, code—breaking could be performed by the investigator calling the IXRS system.

The code-breaking material is also kept at the entity responsible for the "24 hour alert system"; but this system should be used in very exceptional cases only (i.e., unavailability of IXRS system or ity to contact investigator and/or site staff). The igators will be ed by the sanofi—aventis clinical ring team about the availability of the local code—breaking material.

A patient card, including the relevant “24 hour alert system” telephone number will be provided to every t who participates in the study.

If the blind is broken, the Investigator will document the date of opening and reason for code breaking in source data.

In case the blind code is broken, the treatment with the lixisenatide (or placebo) investigational product should be permanently discontinued, and the patient handled according to the procedure described in Section HA. The Investigator must document the date, time of day and reason for code breaking. In case of SAE, the instructions for SAE reporting are to be followed (please refer to Section 10.2.2). 8.9 RESPONSIBILITIES The igator, the clinical site pharmacist, or other personnel allowed to store and dispense lixisenatide, its placebo and the or pen Opticiick® red by Investigational medicinal product) will be responsible for ensuring that the IMP used in the clinical trial is securely maintained as specified by the Sponsor and in ance with the able regulatory requirements.

All IVIPs shall be dispensed in accordance with the Investigator’s prescription and it is the Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is ined.

Any quality issue d with the receipt or use of lixisenatide and its placebo provided by the sponsor (deficiency in condition, packaging, appearance, pertaining documentation, labeling, expiration date, etc.) or OptiCIick® should be promptly notified to the Sponsor, who will initiate a complaint procedure.

A potential defect in the quality of IL I provided by the sponsor may prompt to initiation of a recall procedure by the Sponsor. In this case, the Investigator will be sible for promptly addressing any request made by the Sponsor, in order to recall IMP and eliminate potential hazards.

Under no circumstances will the Investigator supply natide and its placebo provided by the Sponsor to a third party, allow the IMP provided by the Sponsor to be used other than as directed by this clinical trial protocol, or dispose of IMP provided by the Sponsor in any other manner. 8.10 CONCOMITANT TREATMENT Specific treatments, which are ongoing before the study and/or prescribed or changed during the study, must be recorded in the CRF and Source ata (please refer to Section 12.2 ). 8.10.1 Concomitant Diabetes y Patients may be ed with metformin background therapy at a stable dose (210%) for at least 4 weeks prior to randomization). The min dose should be kept unchanged hout the study. It should be administered according to the approved label. 8.10.2 Prohibited concomitant therapy The following drugs dy listed as exclusion criteria, see Section 7.3 ) are not permitted during the study (up to the end—of study visit): 1. Any other any oral or inj ectable antidiabetic or hypoglycemic agents other than metformin (e. g., alpha glucosidase inhibitor, exenatide, DPP—IV inhibitors, insulin, TZD, SU etc.) 2. Systemic glucocorticoids (excluding topical application or inhaled forms) administered for one week or more should be discontinued within 3 months prior to the time of screening. 8.10.3 Permitted concomitant therapy Any therapy other than the prohibited concomitant therapy described above, is d and has to be recordedin the source data (please refer to 12.2) and the e——.CRF Note: For oral treatments that are dependent on threshold concentrationsfor efficacy, such as contraceptives (pill) and otics, patients should be advised to take those treatments at least 1 hour before study drug injection or about 11 hours after study drug injection. 8.11 ENT ACCOUNTABILITY AND ANCE The independent person designed by the investigational site (see Section 8.4) will document dates, time and dose of each self injection of lixisenatide and o and the oral daily dose of metforrnin, if any and will complete the appropriate “Treatment Log Form”.

The Monitoring Team in charge of the study then checks the CRF data by comparing them with the date and time of IMP. 8.12 RETURN AND/OR DESTRUCTlON OF TREATMENTS Investigational medicinal product reconciliation must be performed at the site or CRO by the Pharmacist or other personnel allowed and the monitoring team using ent log forms and documented on center IMP inventory countersigned by the Pharmacist /Investigator and the monitoring team.

A written authorization for destruction will be given by the clinical trial team once the IMP reconciliation is ed. This destruction can be performed at site depending on P specificities and local requirements or IMP can be returned to the Sponsor for destruction. 9 ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 9.1 PHARMACODYNAMICS All pharmacodynamics parameters Will be med by a Central Laboratory. Detailed ation on sample drawing, management and analysis will be provided. 0 Plasma glucose concentrations 0 Insulin, C—peptide and glucagon plasma concentrations (see study and period flow charts for detailed ment schedule) 9.1.1 Assessment methods Plasma glucose, insulin, C—peptide and glucagon are to be sampled at pre-specified times and determined by specific validated . The exact time of sample collection must be recorded on the CRF. l procedures for storage and shipping ofpharmacodynamic samples will be described in a separate technical manual provided by the l Laboratory. 9.1.2 Pharmacodynamic parameters 9. 1.2. 1 Primary parameter(s) o GLU— AUC0230 -4230 after each lixisenatide dose (5 ug, 10 ug) compared to placebo GLU-AUCO:30-4;30hI area under the plasma glucose concentration time profile from time of the standardized breakfast start (30 min after IMP injection and pre-meal plasma glucose =T05) until 4 hours later (T45) subtracting the pre—meal value. AUC will be calculated using the trapezoidal rule. 9. 1.2.2 ary parameter(s) - randial plasma glucose (PPG) excursion after each lixisenatide dose stration (5 pg, 10 ug) compared to placebo PPG excursion Will be calculated from the difference between the maximum after the standardized breakfast and before lunch minus the pre-meal plasma glucose (T05).

- AUCOQO 4:30 of insulin, C—peptide and glucagon concentrations after each lixisenatide dose (5 pg, 10 ug) compared to placebo: The area under the concentration time profile from time of standardized breakfast start (30 min after IIVIP injection and pre-meal plasma glucose =T05) until 4 hours later (T45). AUC will be calculated using the trapezoidal rule. 9.1.3 Assessment schedule The assessment timing can be found in the period flow chart (please refer to Section 1.3 and Section 1.4 Table 3 — Number of samples Plasma Insulin, C- Glucagon Glucose peptide By t/ ing 1 1a 0 By patient per Period 8 7 7 Total by patient 25 22 21 Total for study, n: 24 tsb 600 528 504 a C-peptide only b to be added replacement patients, — if any 9.2 SAFETY 9.2.1 Baseline demographic characteristics: Baseline demographic characteristics will consist of: 1. Age (years) 2. Height (cm) 3. Body mass index 4. Gender . Tanner staging ning only) The Tanner stages are stages (5 stages) of physical development in children, adolescents, and adults (9, (10). The stages‘define physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, and development of pubic hair. Due to natural variation, individuals pass through the Tanner stages at different rates, ing in particular on the timing of puberty. The Tanner stages will be used to assist in defining females of childbearing potential during the ing physical examination. ' 6. Diabetes history including :1 — Date of the diagnosis of type 2 diabetes — ormin co—administered, start date of treatment with metforrnin, daily dose of netforrnin at Baseline 9.2.2 Safety assessment at baseline and during the study The tolerability investigations at baseline and during the study will consist of: 1. Physical examination (includes at a minimum: heart and respiratory auscultation; peripheral arterial pulse; pupil, knee, Achilles, and plantar reflexes; peripheral lymph nodes and abdomen examination).

Body weight (kg); 3. Body temperature (0C); Vital signs (heart rate, systolic and diastolic blood pressure measured after 10 s in supine resting position); Laboratory tests (in fasting conditions for blood samples): Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), Biochemistry: — Plasma/serum electrolytes: sodium potassium, chloride calcium — Liver function. AST, ALT, alkaline phosphatase, glutamyl transferase, total and ated bilirubin .- Renal function: urea, creatinine - lism: glucose, albumin, total proteins, total terol, triglycerides ~ Potential muscle toxicity: creatine phosphokinase — Pancreas: e and lipase — onin (tyroidc-cell tumor marker) at screening only Serum B—HCG only at screening in females of reproductive potential (Tanner stage 2 3) ; Urinary pregnancy test for uating females before each ent period; Plasma follicle—stimulating hormone (FSH), if applicable, at screening to confirm postmenopausal status; Serology tests: hepatitis B antigen, hepatitis C antibodies, anti—HIVl and anti—HIVZ antibodies; ll. Urinalysis: proteins,glucose, erythrocytes, ytes, ketone bodies, and pH.

— Qualitative: A dipstick is to be performed on a freshly voided specimen for qualitative detection using a reagent strip. — tative: A quantitative measurement for glucose, protein, erythrocytes, and leucocytes count will be required in the event that the urine sample test is positive for any of the above parameters by urine dipstick (eg, to confirm any positive dipstick parameter by a quantitative measurement). 12. Urine drug screen: amphetamines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates. 13. Alcohol breath test. 14. Adverse , spontaneously reported by the patient or observed by the Investigator, will be monitored; . Standard d ECGs are recorded after at least 10 minutes in supine position using an electrocardiographic device. The electrodes will be positioned at the same place for each ECG ing throughout the study (attachment sites of the leads Will be marked with an indelible pen).

Each ECG consists of a lO—second recording of the 12 leads simultaneously, leading to. o A single l2—lead ECG (25 mm/s, 10mm/mV) printout with heart rate, PR, QRS, QT, QTc automatic correction evaluation (by the ECG ), ing date, time, initials, and number of the patient, signature of the research physician, and at least 3 complexes for each lead. The Investigator’s medical n and automatic values will be ed in the e-CRF. This printout will be retained at the site.

Warning at each period: Whenever measurements of vital signs, ECG, and blood samples for pharmacokinetics, pharmacodynamics, or safety coincide, the following order will be respected: ECG, Vital signs, codynamics, pharmacokinetics, and then safety samples. In order to respect exact timing of pharmacokinetics samples (refer to flow chart for time Window allowance for pharmacodynamic and pharmacokinetics samples), the other measurements will be done ahead of the scheduled time. The assessment schedule should be adapted to the design of the study. 9.2.3 Anti-lixisenatide antibodies Plasma samples from all patients Will be collected to determine anti-lixisenatide antibodies on Day 1/ period 1 before the first study drug stration only. Procedures for collection, storage, and nt will be provided in a separate manual.

Table 4 - Number of plasma samples for ixisenatide antibodies Anti-lixisenatide antibodies Total by patient (once D1/P1) 1 Total for patients (n=24) 24 Table 5 - Bioanalytical method Analyte Anti- Lixisenatide antibodies Matrix Plasma Analytical que BIAcore Lower Limit of Quantification cut—off Assay Range not relevant Assay Volume 100 pL Site of Bioanaiysis Dept. of Disposition, Safety and Animal ch (DSAR), sanofi aventis, urt Method Reference RPSMPK-DOHO754—BMi—EN-EOi 9.3 PHARMACOKINETICS 9.3.1 Sampling times The sampling times for blood tion can be found in the period flow chart (please refer to Section 1.3 and Section 1.4). 9.3.2 Number of pharmacokinetic samples Table 6 — Number of plasma samples for AVEOO‘iO PK AVE0010 By patient per period 8 Total by patient (X3 periods) 24 Total for patients n=24 (up to 36) 24* 24: 576 (up to 864) 9.3.3 Sample handling procedure for pharmacokinetic samples Procedures for collection, storage, and shipment will be provided in a separate manual. 9.3.4 Bioanalytical methods All iixisenatide plasma samples from patients having ed natide were analyzed as described in Table 7, with a lower limit of quantification.

Table 7- Summary of bioanalytical method WWW-—ytebtisenatide Matrix Plasma Analytical technique Double-antibody sandwich ELlSA Lower limit of quantification 5.5 pg/mL Assay volume 120 uL Site of bioanalysis Biomarker/Biologicals, DSAR, sanofi aventis, Frankfurt Method reference DOH1154 9.3.5 Pharmacokinetic parameters Lixisenatide plasma concentrations at predefined timepoints will be documented. The pharmacokinetic parameters will be ated, using non-compartmental methods for lixisenatide plasma concentrations after single dose. The parameters will include, but may not be limited to the following.

Table 8 — List of cokinetic parameters and definitions Parameters Drug/Analyte Matrix Definition/Calculation Cmax AVEOOlO Plasma Maximum plasma concentration ed tmax 0 Plasma Time to reach Cmax Area under the plasma concentration versus time curve calculated usmg the AUCiast AVE0010 Plasma trapezoidal method from time zero to the real time Area under the plasma concentration versus time curve extrapolated to infinity according to the following equation: Clast AUG — AUCiast + AUC AVEOO1O Plasma 32 (Clasl is the last quantifiable tration, and A; the rate constant of the terminal phase) Values with a percentage of extrapolation >20% will not be taken into account in the descriptive statistics 9.4 SAMP-E BLOOD VOLUME The approximate total sampled blood volume in children is 144 ml (approximate due to ded blood when catheter is set up at each period). The amount of blood volume per Visit will not exceed 46' mL (the highest at period 1). The approximate total sampled blood volume in adults is 144 mL (approximate due to discarded blood when er is set up at each period). 9.5 MEASURES TO PROTECT NG OF THE TRIAL For the purpose of IMP dispensing and stration and bioanalytical ment of PK and anti-lixisenatide antibody samples, the following persons will be unblinded (refer to section 8.8 for the IMP dispensing procedure'restricted to the independent on-site person of the CRO/investigational centre). A copy of the randomization list will be provided only to the bioanalyst responsible for lixisenatide concentration measurements.

In case of an adverse event, the Investigator should only break the code in exceptional stances when knowledge of the Investigational Product is essential for treating the patient (refer to section 8.8).

Nevertheless, for safety reason, the treatment code will be unblinded for reporting to the health authorities of any suspected cted serious adverse reaction (SUSAR), ie, any serious adverse event that is both unexpected (per the investigator’s brochure) and reasonably associated ‘ with the use of the IMP according to either the judgment of the Investigator and/or the Sponsor.

The ARAC is blinded for the cation of allergic and allergic~like cases (please also refer to Section 6.3.1). ' All persons at —aventis and at any CRO involved in the study including laboratory and eventually pharmacodynamic assessors will be blinded to the randomization code.

PATIENT SAFETY The Investigator is the primary person responsible for taking all clinically relevant decisions on safety issues.

Ifjudged necessary, the opinion of a Specialist should be envisaged in a timely manner (eg, acute renal failure, convulsions, skin rashes, angioedema, cardiac arrest, electrocardiographic modifications, etc).

In case of derrnatologic lesions, the realization of photographs is strongly ended in on to quick Dermatologist advice. .1 ADVERSE EVENT MONITORING All events will be managed and ed in compliance with all applicable regulations, and included in the final clinical study . .2 DEFINITIONS OF ADVERSE EVENTS .2.1 Adverse event An adverse event (AB) is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. 0 Mild = no modification of daily activities and does not e mandatory corrective/symptomatic treatment. 0 Moderate = hinders normal daily activities and/or requires mandatory corrective/symptomatic treatment. 0 Severe : prevents daily activities and requires mandatory corrective/symptomatic treatment. .2.2 Serious adverse event A serious adverse event (SAE) is any rd medical occurrence that at any dose: 0 Results in death, or o Is life—threatening, or Note: The term “life—threatening” in the definition of us” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. o Requires inpatient hospitalization or prolongation of existing hospitalization, or 0 s in persistent or significant disability/incapacity, or o Is a congenital anomaly/birth defect, or o Is a medically important event: — Medical and scientific judgment should be exercised in deciding r expedited ing is appropriate in other situations, such as important medical events that may not be immediately life—threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the ion above.

Note: Examples of such events are intensive treatment in an emergency room or at home for allergic ospasm, blood dyscrasias, convulsions ALT > 3 x ULN + total bilirubin > 2 x ULN or asymptomatic ALTincrease > 10 X ULN or development of drug dependency or drug abuse Unblinding of SUSAR by the Sponsor is described in Section 9.5. .3 OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .3.1 General guidelines for reporting adverse events All AEs, regardless of seriousness or relationship to D/IP, spanning from the signature of the informed t form until the end of the study as defined by the protocol, are to be recorded on the corresponding page(s) or screen(s) of the case report form for included patients. For screen failed ts, recording in the case report form is only performed in case of SAE occurring during the screening period or in case ofAE when some screening procedures expose the patient to safety risks (eg, any substance administered as pretreatment or for phenotyping, invasive tests performed or chronic treatment interrupted).

Whenever possible, diagnosis or single me should be reported d of symptoms. The Investigator should specify the date of onset, intensity (see definitions in Section 10.2.1), action taken with respect to TMP corrective treatment/therapy given, onal igations performed (eg, in the case of derrnatologic lesions photographs are required), outcome, and Investigator’s n as to whether there is a reasonable possibility that the AE was caused by the IMP.

In order to ensure the safety of the ts, the Investigator should take appropriate measures to follow all AEs until clinical recovery is complete and laboratory results have returned to normal, or until ssion has been stabilized, or until death. This may imply that observations will continue beyond the last planned visit per protocol, and that additional investigations may be requested by the monitoring team.

When treatment is prematurely discontinued, the patient’s observations will continue until the end of the study for that patient as defined by the protocol.

Laboratory, vital signs, or ECG abnormalities are to be recorded as A *s only if: symptomatic, and/or requiring either corrective treatment or consultation, and/or leading to IMP/NIMP discontinuation or modification of dosing, and/or fulfilling a seriousness criterion, and/or defined as an AESI. .3.2 Guidelines for reporting s adverse events In the case of a SAE, the Investigator must immediately: These first 4 bullets should be applicable in case of paper case report form used.

ENTER the information d to the serious adverse event in the appropriate s of the e—CRF; the system will automatically send the notification to the monitoring team after approval by the igator within the e—CRF or after a standard delay.

SEND (preferably by fax or e—mail) the photocopy of all examinations carried out and the dates on which these examinations were performed, to the representative of the monitoring team whose name, fax number, and e—mail address appear on the clinical trial protocol.

Care should be taken to ensure that the patient’s identity is protected and the patient‘s identifiers in the clinical trial are properly mentioned on any copy of source document provided to the r. For laboratory results, include the tory normal ranges.

All r data updates should be recorded in the e—CRF as appropriate, and r documentation as well as additional information (for laboratory data, concomitant medication, t status, etc) should be sent (by fax or e—mail) to the monitoring team within 1 g day of knowledge. In addition, any effort should be made to further document within the week (7 days) following initial notification any s adverse event that is fatal or life threatening.

A back—up plan is used (using paper flow) when the e—CRF system does not work.

These next 3 bullets will be applicable in case of e—CRF is used for a %ack—up plan) SEND ( preferably by fax or e-mail) the signed and dated corresponding page(s) in the case report form to the representative of the monitoring team whose name, fax number, and e—mail address appear on the clinical trial protocol.

ATTACH the photocopy of all examinations carried out and the dates on which these examinations were performed. Care should be taken to ensure that the patient’s identity is protected and the t’s identifiers in the clinical trial are properly mentioned on any copy of source documentprovided to the Sponsor. For laboratory results, include the laboratory normal ranges.

All further documentation should be sent to the monitoring team within 1 working day of knowledge. In addition, every effort should be made to further document within the week (7 days) following initial notification any s e event that is fatal or life ening.

Any SAE brought to the attention of the igator at any time after the end of the study for the patient and ered by the Investigator to be caused by the MP with a reasonable possibility, should be reported to the monitoring team. 0.3.3 Guidelines for reporting e events of special interest ”he need for specific monitoring, documentation, and management of AESI are described in this section. “:or each defined adverse events of special interest, consider carefully the need to collect additional specific information that would impact the study and]or the case report form design, such as: Preexisting related condition or lifestyle of interest for the adverse event (eg, habits, cardiovascular risk factor, etc) Expected list of associated signs and symptoms Corrective actions (eg, treatment discontinuation, concomitant treatment, etc) Diagnostic actions (eg, test(s) or procedure(s) results, etc) Additional descriptive factors Sequelae .3.3.1 Reporting of adverse events of l interest with immediate notification For AESI with immediate cation, the Sponsor is to be informed immediately (ie, within 1 working day), as per SAE notification guidelines described in n 10.3 .2, even if a seriousness criterion is not met, using the corresponding pages of the case report form (to be sent) or screens in the e-CRF.

ALT increase 22 x ULN (refer to d decision chart in ix A) _QTc _>_500 ms Tn the event of prolongation of QTc interval (automatic measurement) >500 ms, confirmed by a manual reading by the Investigator or a physician delegated by the Investigator using the Fridericia formula for correcting QT, the patient should be placed under supervision in a specialized setting. Investigational medicinal product administration must be stopped and appropriate blood samples collected. Subsequent ECG monitoring of the patient should then be med on a r and clinically responsible basis until the QTc interval returns to a safe value as determined by the Investigator in agreement with the Sponsor.

Pregnancy ~ Pregnancy occurring in a female patient ed in the clinical trial: Pregnancy will be recorded as an adverse event of special interest with immediate notification in all cases. It will be qualified as a serious adverse event only if meeting one of the seriousness criteria.

- In the event of pregnancy, IMP should or must be discontinued.

— Follow—up of pregnancy will be mandatory until its outcome has been determined.

- Symptomatic overdose with IMP — An overdose (accidental or intentional) with the IMP is an event ted by the Investigator and defined as at least twice of the intended dose within the intended therapeutic interval, adjusted according to the tested drug .3.3.2 Reporting of adverse events of special interest without immediate notification o Asymptomatic overdose with IMP (Refer to Section 10.3.3.1) - Symptomatic hypoglycemia (see definition below) with an accompanying plasma glucose < 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate administration if no plasma glucose measurement is available.

Symptomatic hypoglycemia is defined as an event with clinical symptoms that are considered to result from a hypoglycemic episode (e.g., sweating, palpitations, hunger, restlessness, anxiety, fatigue, irritability, headache, loss of concentration, somnolence, psychiatric or visual disorders, ent sensory or motor s, confusion, convulsions, or coma).

Symptoms with an associated blood glucose ement _>_ 60 mg/dL (3.3 mmol/L) should not be reported as a hypoglycemia.

Symptomatic hypoglycemia is to be ed as an adverse event. It should be ed in the CRF on the specific AE form for symptomatic hypoglycemia. Additional information should be collected on a c symptomatic hypoglycemic event complementary form. 0 Severe symptomatic hypoglycemia Severe symptomatic hypoglycemia is defined as an event with clinical ms that are considered to result from hypoglycemia in which the patient required the ance of another person, because the patient could not treat rself due to acute neurological impairment directly resulting from the hypoglycemic event, and one of the following: — The event was associated with a plasma e level below 36 mg/d J (2.0 mmolIL).

— If no blood glucose measurement is available, then the event was associated with prompt recovery after oral carbohydrate, enous glucose, or glucagon administration.

The ion of severe symptomatic hypoglycemia includes all es in which neurological impairment was severe enough to prevent self—treatment and which were thus thought to place patients at risk for injury to themselves or . Note that “requires assistance” means that the patient could not help f or herself. Someone being kind that assists spontaneously the patient when not necessary does not qualify as.“requires assistance.” Severe symptomatic hypoglycemia will be qualified as an SAE only if it fiilfills SAE criteria.

Suspected Pancreatitis In case of severe, persistent abdominal pain, which can radiate to the back, often with teristic positional features, with possible occurrence of nausea, vomiting, fever and leucocytosis, r measurement of amylase and lipase should be performed. The diagnosis of pancreatitis may be supposed also if other causes of abdominal pain are excluded (i.e., gallbladder e, etc) and elevated amylase/lipase is seen and in addition pancreatic changes are seen on ultrasound and/or CT or MRI (with contrast, as appropriate).

Pancreatic enzymes (amylase, lipase) must be measured. 9Amylase and lipase values greater than 2-fold ULN should be repeated within 7 days.

-)Amylase and lipase values greater than 3—fold ULN should be repeated Within 48 hours.

If the value remains above 2—fold ULN, it should be repeated weekly until it is less than 2— fold ULN. e and lipase elevations without associated clinical symptoms should receive a gastroenterologic evaluation with additional imaging, as appropriate. All the laboratory or clinical documentations should be collected. As soon as there are signs, symptoms and results of investigations exploring ted pancreatitis (eg, laboratory results, imaging reports, gastroenterologist’s evaluations, etc) related to suspected pancreatitis, the investigator must document and report them on a specific e—CRF form.

With any diagnosis of acute pancreatitis, the investigatidnal ent and other potentially suspect drugs should be stopped and the patient followed further ally Allergic or allergic—like reaction In case a patient experiences an allergic reaction or an allergic—like reaction this has to be reported as an e event. Additional ation is collected on specific allergic reaction forms. Allergic, or possible allergic reactions will be adjudicated by the Allergic on Assessment Committee (ARAC, Section 6.3.1 ). .3.4 Guidelines for management of specific laboratory abnormalities Once the patient is included in the al trial, the ing laboratory abnormalities must be monitored, documented, and managed i. ” o Neutropenia o Thrombocytopenia 0 Acute renal insufficiency o Suspicion of rhabdornyolysis .4 OBLIGATIONS OF THE SPONSOR During the course of the study, the Sponsor will report in an expedited manner: 0 All SAEs that are both unexpected and at least ably related to the IVIP (SUSAR), to the Health Authorities, lRB/IECS as appropriate and to the Investigators. o All SAEs that are expected and at least reasonably related to the [MIPS to the Health Authorities, according to local regulations. 11 HANDLING OF PATIENT WITHDRAWAL The basis of reason for treatment withdrawal should be identified. 11.1 -IST OF TREATMENT WITHDRAWAL CRITERIA Refer to Section 10.3 Pregnaney lead to permanent treatment discontinuation in all cases (Refer to Section 11.2 REASONS FOR ENT WITH DRAWAL ts can withdraw from the treatment if they decide to do so, at any time, and for any reason, or this may be the Investigator’s on. 11.3 EMENTS OF PATIENTS A patient who prematurely end his/her treatment study participation after the start of the baseline period and who received study drug can be replaced in order to obtain as far as possible 12 completed patients per population. In the event of discontinuation due to occurrence of AE, the replacement will be discussed between the Investigator and the Sponsor. Replacement patients must meet all inclusion and exclusion criteria.

The replacement patients will have a different t number, by adding 500 to the number of patient ed. 11.4 FOLLOW-UP URE FOR TREATMENT WITH DRAWAL All study treatment withdrawals should be recorded by the Investigator on the appropriate case report form pages or screens for e—CRF when considered as confirmed.

If possible, patients are to be ed using the procedure planned for the end—of—study Visit, including a pharmacokinetic sample if appropriate.

For any patient who fails to return to the site, the Investigator should make every effort to recontact the patient (eg, contact the patient’s family or private physician, review available registries or health care database), and to ine his/her health , including at least his/her vital . Attempts to contact the patient must be documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a registered letter).

Patients Withdrawn fiom the study must not be reincluded in the study. Their inclusion and treatment numbers must not be reused. 12 STUDY PROCEDURES 12.1 VISIT SCHEDULE The study consists of a screening period up to 4 weeks followed by a randomized, —blind, 3 crossover treatment periods l~7 days apart. Each period will last one day only (but, if all examinations and tests to be performed before dosing on Day 1, are not possible, a visit on Day —1 (afternoon) at the ience of patient and the possibilities of the investigational site (e.g., an institutionalization / an accommodation for one night before Day 1 at each period).

At each treatment period, the patients will receive a subcutaneously injected single dose of either pg or 10 ug lixisenatide with 5 ug preceding the 10 ug dose level or volume matched placebo (50 uL or 100 uL). The end—of—study visit is scheduled between Day 2 and Day 7 of the treatment period 3.

All the in—clinic (Day 1) visits should take place in the morning at approximately the same time. 12.1.1 Screening procedures Screening procedures will be carried out within 30 days prior to inclusion but blood sampling should be done at latest on Day --25 to obtain the results before the randomization (Dayl).

For paediatric study population: At this first contact the study will be explained to the patient’s parents or legal guardian (hereinafter the “paren ”). The parent will receive verbal information concerning the aims and methods of the study, its constraints and risks, and the study duration. Written informed consent must be signed by the parent prior to any investigations. In addition, ion of Assent Form will be signed by minor patients or Informed Consent Form will be signed by emancipated or mature minors (defined by local lows).

For adult study population: The patient will receive ation on the study obj ective(s) and ures fiom the Investigator. The adult patient will have to sign the informed consent prior to any action related to the study.

For all patients, the screening visit will include the following investigations (refer to Section 9.2): 1. Demographics: age, sex, race, height, body weight in kg, BMI [Body Mass Index = weight (in kg)/height (in cm) 21; 2. For paediatric population: tanner g ning only). 3. Relevant medical history ing personal or familial history of medullary thyroid cancer (MTC) or a c condition that predisposes to MTC, t’s y medical y, risk factors for pancreatitis [c.g, habits of alcohol consumption (none, 3 2 drinks / day or > 2)] and al history; Physical ation (cardiovascular system, chest and lungs, thyroid, abdomen, nervous system, skin and mucosae, and musculo—skeletal system); . History of type 2 diabetes history (date of the diagnosis of diabetes); Concomitant and previous medication including antidiabetic treatments in the last 3 months prior to study entry start date of treatment with metformin if administered, daily dose of metforrnin at Baseline (refer to the inclusion criteria 101, Section 7.2) ' 1CG (standard l2—lead), Vital signs ements (heart rate, systolic and diastolic blood pressure measured after 10 minutes rest in supine position); Body temperature Urine drug screen: amphetamines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates; . l test; ll. Laboratory tests in fasting condition with hematology and clinical chemistry including serum test (anti—L42, and anti—GAD), fasting C—peptide, HbAl c, fasting plasma , antibody glucose, calcitonin, serologies itis B n, hepatitis C antibodies, anti-HIVl and anti-HIV2 antibodies), urinalysis, B-HCG blood test solely in females of reproductive potential (Tanner Stage 2 3), serum FSH (in adult women, if applicable, to confirm postmenopausal status); 12. Each centre will call IXRS to receive an incremental identification number of their patient corresponding to his/her order of enrollment in the study (refer to Section 8.5); Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for the ion visit (Day 1). 12.1.2 Description by type of visit 12.1.2.1 Treatment period 1 Inclusion procedures The inclusion Visit will be d out on the day of inclusion (Day 1) and will include the following investigations (refer to Section 9.2): 1. For safety and practical reasons, for tric population, topical application of cream or other anesthesic local application (e.g.; EMLA®) can be applied on the forearm approximately 1 hour before the venipuncture at the site where the catheter for blood ng will be in place for ng pain in patients, especially in children; Physical examination: medical history, weight, and body temperature; . ECG and vital signs measurements; 4. Urinary pregnancy test in females with reproductive potential (Tanner stage 2 3); . Urine drug screen: amines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates; 6. Alcohol test; Rechecking of any baseline parameter is to be limited to one time except when the ement has not been obtained in accurate conditions. The last value should be considered, as the baseline value and reported in the case report form. If a parameter at baseline is part of specific inclusion criteria, king is not permitted; one abnormal value is cause for exclusion.

Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for inclusion in the study. Final inclusion and randomization will be performed just before the IMP administration on Day 1.

'For safety and practical reasons, approximately 15 minutes before blood sampling, an indwelling catheter may be inserted in a peripheral vein of the forearm in order to obtain blood s. etween samplings, the catheter will be locked with a mandrel. Heparin use during blood draws is NOT allowed (to avoid any potential contamination with heparin which may interfere with the drug/antibody assays). 0.9% saline can be used to flush the collection catheter. Prior to collection of the blood sample Via an indwelling catheter, 05 mL of blood has to be drawn and discarded to avoid on.

When the patient is confirmed for the study inclusion, the treatment period will include the following investigations (refer to n 9.2): 1. According to the procedure described in Section 85, the Pharmacist or the Independent person will call IXRS to receive the treatment kit number allocation; 2. Blood sampling for anti—lixisenatide antibodies test before the IMP stration; 3. 0.5h before breakfast, self injection of lixisenatide at the dose of 5 pg (5 Units indicated on OptiClick®) or lOug QD (10 Units indicated on OptiClick®) or placebo (50 uL or 100 uL), under the observation of the medically qualified designee. However, for blinding purposes the on—site administration of lixisenatide or its placebo will therefore be performed by an independent person who is not a member of the clinical study team at the CR0 or investigational site; 4. rdized breakfast (refer to n 8.4 30 minutes after the first , Appendiij) given blood codynamic sampling, corresponding to the pre—specified time T0.5h.; . Blood ng for the evaluation of plasma glucose, insulin, ide- and glucagon starting between approximately 07:30 and 09:00 (T0 before the study drug administration) with 7 (8 for plasma e) pre— specified timepoints: T0, T05 (just before breakfast), Tl, T15, T2 (plasma glucose only), T25, T35, and T45 e ; 6. Blood sampling for PK starting between approximately 07:30 and 09:00 (T0, before the study drug administration) and at 7 pre— specified timepoints after dosing: T05 (just before breakfast), Tl, T15, T25, T35, T45 (before lunch) and T65; 7. Vital signs measurements at T25 and T65 8. Physical examination : before discharge (T65); 9. Recording of e events and concomitant medication, if any; . Patients will be discharged after a complete review of the available safety data by the Investigator; 11. Patients will be instructed to come back to the study site within 8 days (between Day 2 and Day 8); 12.1.2.2 Treatment periods 2 and 3 The treatment period will include the following investigations (refer to Section 9.2): l. For safety and practical reasons, for tric population, topical atch (eg, EMLA®) a pain inpatients, especially in children. w, x M . m ; Recording of adverse events and concomitant medication, if any; Urine drug screen: amphetamines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates before IMP administration ; Alcohol test before IMP administration; Physical examination including body , body temperature and the respect of the adherence to study ctions before IMP administration; ECG and vital signs ements before IMP administration ; Urinary pregnancy test in females with uctive potential r stage 2 3) before IMP administration; 0.5h before breakfast, self injection of liXisenatide at the dose of 5 ug (5 Units ted on OptiClick®) or lOug QD (10 Units indicated on OptiClick®) or placebo (50 uI. or 100 uL), under the observation of the medically qualified designee. However, for blinding purposes the on—site administration of lixisenatide or its placebo will therefore be performed by an independent person who is not a member of the clinical study team at the CRO or investigational site; Standardized breakfast (refer to n 8.1), given 30 minutes after the first blood pharrnacodynamic sampling, corresponding to the pie-specified time ; . Blood sampling for the evaluation ofplasma glucose, insulin, C—peptide- and glucagon starting between approximately 07:30 and 09:00 (T0 before the study drug administration) with 7 (8 for plasma glucose) pre— specified timepoints: T0, T05 (just before breakfast), T1, T15, T2 (plasma glucose only), T25, T35, and T45 (before ; ll. Blood ng for PK starting approximately between 07:30 and 09:00 (T0, before the study drug administration) and at 7 pre— specified timepoints after dosing: T05 (just before breakfast), T1, T15, T25, T35, T45 (before lunch) and T65; 12. Vital signs measurements at T2 and T65 13f“CG and physical examination med at T65 ; 14. Recording of adverse events and concomitant medication, if any; . Patients will be discharged after a complete review of the available safety data by the Investigator; 16. At period 3, each centre will call lXRS to inform that all treatments have been stered (end of the treatment period) for the given patient; 17. Patient will be instructed to come back to the study site within 8 days (between Day 2 and Day 8); > Ambulatory peri0d(s) During the study, patients should immediately contact the Investigator or one of the clinical unit managers in the event of any ained symptom or any unexpected effect or event occurring during the study. For this , patients will be informed that they can contact the clinical unit by telephone 24 hours a day. Patients must give the Investigator a telephone number Where they can be contacted in an emergency. Patients must carry with them, during ambulatory study period(s), the t card indicating the patient number and the emergency telephone number provided by the study site. 12. 1.2.3 End-of-study visit The —study visit will be performed between 1 to 6 days after last dosing (D2 to )7 afier Period 3); it will include the following investigations (refer to Section 9.2): l. Physical examination including body weight; 2 . ECG and vital signs measurements; 3 Laboratory tests in g conditions with hematology and clinical chemistry; 4. Jrinalysis; ’{ecording of adverse events and concomitant medication, if any; 6 . TXRS call for the end of the study for the patient given; 12.1.3 Study restriction(s) The s of the glycemic index (GI) of carbohydrate eaten the previous night on the glycaemic response to a standard test meal eaten subsequently in the morning (breakfast) have been described (ll, 12). As far as possible, recommendation will be given to patient to eat a pasta course at the dinner preceding Day 1 of each period.

After the dinner on Day—l, patients should stay in fasted conditions for at least 8 hours (food and drink are not d except water) up to the standardized test meal.

At each site visit, on Day 1 of each period, patients should refrain from drinking alcohol, tea, coffee, chocolate, quinine, or ne—containing beverages. Consumption of citrus fiuits and their juices is prohibited during the treatment period (Dayl of each period). Smoking and tobacco use will not be allowed from 1 day prior to institutionalization throughout the study duration until the end—of—study Visit. Patients will receive standardized meal test (liquid test for breakfast) (see Section 8.1).

Patients will be requested to follow a stable lifestyle with no intensive physical ty for the on of the study until the end~of~study visit. 12.2 DEFINITION OF SOURCE DATA All evaluations that are reported in the case report form must be supported by appropriately identified source documentation. 0 Agreement and signature of informed consent mentioning the study identification, 0 Patient identification, last participation in a clinical trial, medical y, associated diseases, and data d to the studied pathology, 0 Contraception method for women of childbearing potential, 0 Previous and concomitant medication, 0 Study identification, 0 Dates of administration and doses of lixisenatide or placebo, 0 Start date of metformin if patients are treated with, and daily dose at screening, 0 Dates of Visits and assessments including the examination report, 0 Vital signs, height, body weight, 0 laboratory assessments, ECG; o Pharmacodynamic and cokinetic time points 0 start/end of meals a ECG records signed and dated, 0 Adverse events and follow—up: c In case of SAE, the site should file in the source document at least copies of the hospitalization s (if appropriate) and any relevant examination reports documenting the follow—up of the SAE. ‘ 0 Date of ure study discontinuation (if any) and reason.

Source documentation may be found in the following: 0 Patient’ s identity, 0 Medical history, 0 Nursing notes, 0 Physician’s notes, 0 Patient’s diaries. o starflend of ECG 13 STATISTICAL CONSIDERATIONS The material in Section 13 of the clinical trial protocol constitutes the statistical analysis plan for the study. Should this plan need revision during the study to accommodate clinical trial protocol amendments or to adapt to unexpected issues in study execution and data that affect planned es, a statistical analysis plan will be issued prior to database lock. 13..1 DETERMINATION OF SAMP c SI? Illll Power ation was based on the results of the double—blind, placebo—controlled, single—dose, study AV £0010/01-016 performed in patients with type 2 diabetes. The following table (Table ll) summarizes the results of the comparison of single doses of 3 ug and 10 ug lixisenatide with placebo for the AUCl—Sh of plasma glucose. It can be assumed that the effect of pg is more pronounced than in 3 pg.

Table 11 - Results from study AVE0010 l 01-016 - Statistical Analysis of Area Under Curve for plasma Glucose: Pairwise Comparisons Between Dose Groups 3 and 5 pg versus placebo Dose N Mean difference to Placebo Standard Error (mg/d1) (mg/dl) 3 pg 4 154 50 pg 4 347 50 Power calculation was performed for a 2-group t—test (Crossover ANOVA) for differences in means n active treatment and placebo for different standard deviations of 70, 100 and 150 mg.h/dL to take into consideration a possible higher variation in paediatrics than in adults. A type 1 error alpha = 5 % and a roni corrected alpha = 2.5 % was used for the power calculation.

Table 12 - Power ation for Plasma Glucose AUC - alpha = 5 % Power ation for 12 patients with alpha = 5% for blood glucose AUC Dose levels 5119 10:19 Spa 10119 5119 10ug Within—patient 70 70 100 100 150 150 standard deviation (mg.h/dL) ence in means 155 350 155 350 155 350 (mg.h/dL) Power (%) 99 99 92 99 62 99 TotalN 12 12 12 12 12 12 2-sided t-test over ANOVA) for difference of means Table 13 — alpha = 2.5 % - Power calculation for Blood Glucose AUC Power calculation for 12 patients with alpha = 2.5% for plasma e AUC Dose levels 5119 10119 599 10119 599 10119 Within—patient standard 70 70 100 100 150 150 ion (mg.h/dL) Difference in means 155 350 155 350 155 350 (m.hg/dL) Power (%) 99 99 85 99 48 99 Total N 12 12 1'2 12 12 12 H I i i i H l—test( CrossoerMDAVA) fortitediffrencf‘ means With a total of 12 patients, a crossover‘design would have 99% power to detect a difference in the mean corrected plasma glucose—AUC0;30h-4;30h, between lixisenatide and placebo of 19.43 mmol.h/L (350 mg.h/dL) assuming a —standard deviation of 5.55 mmol.h/L (100 mg.h/clL), using a 2—group t—test with a 0.05 two—sided significance level, and 92% power to detect a difference in means of 8.60 mmol.h/L (155 mg.h/dL). Additional details are provided. in 16-1—1-protocol [13]. 13.2 PATIENT DESCRIPTION 13.2.1 Disposition of patients A detailed ption of patient accountability including count of patients randomized and treated (i.e. having a randomization number assigned and who received at least one administration of the Investigational Medicinal Product (1MP) ), and who discontinued along with the main reason for discontinuation and who requested treatment discontinuation, will be generated by tion (paediatric and adult) and ent group within population.

Patient disposition at the end—of—study (EOS) visit will be presented in a g sorted by population and patient within sequence, including patients’ status (alive or dead) at the end of the study with the date of last study drug intake, date of last available information and method of contact, date of ‘TOS visit, reason for discontinuation, and r the blind was broken on site at time of discontinuation. All withdrawals from the study, taking place on or after IMP administration, will be fully documented in the body of the CSR.

In case of code broken for medical and accidental reasons on site, a listing of concerned patients will be provided, specifying the reason (AE/SAE or other), the date and time of code breaking and the person who broke the code.

A listing of comments on the e—CRF related to igational product compliance and dosing, safety (adverse events, tory, vital signs and ECG data) or other comments will be provided. 13.2.2 Protocol deviations During the review of the database, the ance with the protocol will be examined with regard to inclusion and exclusion criteria, treatment compliance, prohibited therapies, and timing and availability of planned assessments. Protocol deviations will be identified by the study team before database lock and listed in the Data Review and Surveillance Report, including missing data and study drug discontinuations, and classified as important or other deviations.

Individual deviations to inclusion and exclusion criteria as reported by the Investigator will be listed.

If any, important deviations will be listed by population (paediatric, adult) and patient and/or described in the body of the al study report. 13.3 ANALYSIS POPULATION A summary table of count of patients included in each analysis population (pharrnacodynamic, pharmacokinetic and safety) will be provided by population (paediatric and adult) and by ent within population. All exclusions from any is populations will be fully documented in the CSR.

Safety population All randomized patients d to the IMP (regardless of the amount of treatment administered) will be ed in the safety population.

Pharmacokinetics population Two pharmacokinetic (PK) populations will be considered. -— ‘he full analyses tion including all patients without any major deviations related to study drug administration, and for whom any pharmacokinetic ters are available. — he evaluable population including patients from full analyses population who completed both lixisenatide treatments in compliance with the protocol and having blood samples for reliable evaluation. ‘ The primary PK population is the evaluable tion. The full analyses population will only be analyzed if the number of evaluable patients differ by more than 3 (>= 3).

The placebo treatment period can not be ered.

Pharmacodynamic population Two pharmacodynamic (PD) tions will be considered: — The full analyses population including all randomized and treated patients without any important deviation d to IMP administration for whom the primary PD data is ered sufficient and interpretable.

— The evaluable PD population including patients from the full es population who completed all 3 treatment s in compliance with the protocol and having blood s for reliable evaluation.

Patients will be analyzed as treated. The primary PD population is the evaluable population. The full analyses population will only be analyzed if the number of evaluable patients differ by more than 3 (>= 3). 13.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 13.4.1 t demographic characteristics, medical history and diagnoses Continuous variables (age, weight, BMI, duration of es, duration of anti—diabetic treatment, age at onset of diabetes ) and qualitative variables (gender, race, pubertal stage) will be summarized by descriptive statistics by treatment group within population (paediatric, adult), and for all patients for the safety tion and for the P ) and/or PK population, if relevant.

All demographic data will be listed. 13.4.2 ne codynamic parameters The baseline will be the jay 1 pre—dose measurement of each parameter. 13.4.3 Baseline safety parameters Baseline for safety parameters will be defined as the last available and evaluable parameter value before and closest to the first closing on Day—l/Day l in each period for vital sign parameters and for {CG parameters and during screening for laboratory data.

Baseline definitions specific to each type of safety parameter will be detailed in corresponding Sections 13.8.3.2 to 13.8.5). 13.5 EXTENT OF STUDY TREATMENT EXDOSURE AND COMPLIANCE A summary table presenting the exposure of treatment (ie, duration of IMP in days, defined by: end date of administration — start date of stration + 1) will be provided by treatment group within population, on the safety population.

The following listings will be provided: 0 Details of drug dosing l treatment received, date and time of HVIP intake, route of administration, intended and actual dose received) o The patients receiving D/IP fiom specified batch o Randomization scheme 0 A listing of meal data. 13.6 PRIORICONCOMITANT M EDlCATION/THERAPY Previous medications and itant treatments will be coded according to the World Health Organization — Drug Dictionary (W IO—DD, last version available). Patients who took medications that were stopped before the first 1MP dosing, and/or patients who received concomitant treatments with the IMP will be listed. In addition, a separate g of the previous anti~diabetic medication will be provided. 13.7 ANALYSIS OF PHARMACODYNAMIC VARIABLES 13.7.1 Description of pharmacodynamic variable(s The pharrnacodynamic data will be collected and managed by a Central Laboratory. The pharmacodynamic parameters will be derived from using plasma glucose, insulin, C—peptide and glucagon trations.

All the pharmacodynamic analyses will be performed using the evaluable PD population. Ifthe evaluable PD population differs by more than 3 patients (>=3) then the full analyses tion will be ed in on.

The paediatric and the adult population will be analyzed separately. Results will be compared between paediatrics and adults descriptively. 13. 7. 1. 1 Primary variable The following PD le will be considered as primary: — (GLU-AUCO;30_4;30h) calculated as the area under the plasma glucose concentration time curve from time of breakfast start (30 min after IMP injection i.e. T0.5h) until 4 hours later ) subtracting the pre—meal value T0.5.

The trapezoidal rule will be used to calculate the AUC. 13.7.1.2 Secondary variables The following les will be used as secondary for codynamic es: — Post-prandial plasma glucose (PPG) excursion: PPG excursion will be calculated from the difference betWeen the maximum after the standardized breakfast and before lunch subtracting the pre—meal plasma glucose (T05).

~ AUC0130 —4:30 of insulin, C—peptide and glucagon concentrations: the area under the concentration time profile from time of standardized breakfast start (30 min after injection and pre—meal plasma glucose = T05) until 4 hours later (T45). AUC will be calculated using the trapezoidal rule. 13.7.2 Primary analysis GLU—AUCO:30—4:30h will be analyzed using the following analyses of covariance (ANCOVA) model with treatment (lixisenatide 5 ng and 10 ug and o pooled across both placebo formulations), sequence (6 ces), period (1, 2 and 3) as fixed effects, and patient-within- sequence as random effect, and the T05h plasma glucose concentration as covariate using SAS® PROC MIXED procedure: GLU—AUC0230—4z30h = Treatment + period + sequence + patient (sequence) + plasma glucose T05 + error In case the number of patients in at least one sequence is too small, the model has to be adapted by removing the sequence effect.

The least square mean differences between treatment groups and the corresponding 90% confidence interval (CI) will be calculated within the linear mixed model framework. A significance level ofp< 0.05 will be used. No adjustment for multiplicity will be performed. 13.7.3 ary analysis/analysis of secondary variables The secondary acodynamic parameters PPG and the AUCs of n, C—peptide, and glucagon will be analyzed using the same statistical model as described above with the corresponding T05 h values as covariates.

GLU—AUC0230—4z30h, PPG and the AUCs of insulin, C—peptide and glucagon will be compared between the paediatric and adult tions descriptively.

Individual and mean (:SEM) profiles of plasma glucose, insulin, C-peptide and glucagon will be plotted by population and treatment group Raw data and derived parameters will be listed. 13.8 ANALYSIS OF SAFETY DATA The safety evaluation will be based upon the review of the individual values (clinically significant abnormalities), descriptive statistics (summary , graphics) and if needed on statistical is (appropriate estimations, confidence intervals), following the sanofi—aventis guideline for reporting e 1 s rizing and reporting Clinical pharmacology trial data”. All the safety analyses will be performed using the safety population.

For all safety data, the observation period will be divided into three segments: 0 The pre—treatment phase defined as the time between the patients give informed consent and the first IMP administration. 0 The on—treatinent phase defined as the time from the first IMP administration up to 24 hours after last administration of IMP (included). 0 The reatment phase will be defined as the time after the on—treatment phase.

All analyses will be based on the on—treatment phase.

For the adults a sanofi-aventis specific list of criteria defining “Potentially Clinical Significant Abnormalities” (PCSAs) will be used for the statistical analysis and presentation of tory parameters, vital signs and ECG data. The last version for definition of PCSAs available at the time of se lock will be used. . 13.8.1 Adverse events Adverse events will be coded according to the Medical ictionary for Regulatory Activities (MedDRA, last available version).

They will be fied into predefined rd categories according to chronological criteria: 0 Pre—treatment AEs are defined as AEs that occurred, worsened (according to investigator opinion) or became s during the pre—treatment phase. 0 Treatment emergent AEs (TEAEs) are defined as AEs that occurred or worsened or became serious during the on—treatment phase. o Post—treatment AEs are defined as A is that occurred ed or became serious during the post-treatment phase.

Treatment emergent adverse events will be assigned to the treatment group ed at the time of the AB onset.

If the start date (or time) of an A 4 is incomplete or missing, then the AB will be considered as a TEAE unless a partial date (or time) shows it as a pre— or post—treatment event. If a TEAE develops on one period and worsens in the following period, it will be considered treatment emergent for both periods.

All A 1s reported in the study will be listed, sorted by population (paediatric, adult) and patient, onset date and time. heless, the analyses of the AEs will focus on the T *‘Ab‘s. 13.8.1.1 Treatment-emergent adverse events The following ncy distributions of TEAEs (incidence tables) will be provided for the safety population by treatment Within population for the total on—treatrnent period: e Overview ofTEAE: Number and tage of patients with at least one TEAE, severe TEAEs, s TEAEs, TEAES g to treatment tinuation and, if any occurred, TEAEs leading to death a Summary of treatment—emergent adverse events by primary system organ class and preferred term — Number and percentage of patients with at least one TEAE a Summary of treatment—emergent adverse events by primary system organ class and preferred term ~ Number and percentage of patients and the number of events 0 Listing of patients presenting treatment emergent e events by population, treatment, system organ class and preferred term 13.8.1.2 Deaths, serious, and other significant adverse events Deaths, serious ABS, and other significant AEs (eg, related to specific laboratory abnormalities) will be listed dually and described in the study report in detail. 13.8.1.3 Adverse events leading to treatment discontinuation In case of any occurrences, individual t listings will be generated for all adverse events g to treatment discontinuation. 13.8.1.4 Allergic reactions Listings for allergic reactions Any cases of allergic reaction will be documented as e events with detailed complementary information. A listing of individual data (separate from the listing of all adverse events) will be provided, sorted by patient, onset date and time, irrespective of the tion of the on—treatment phase, including specifically ption of the adverse event, symptoms of the adverse event, possible etiologies, actions taken, vital signs measurements (at outset, during reaction and at recovery) and a ption of the allergic or allergic—like event.

The assessment of all these cases by the Allergic Reaction Assessment Committee (ARAC) will be also listed, including notably Whether the event reported constitutes an allergic reaction, and if it does, its diagnosis and severity grade.

All cases will be described in detail in the CSR.

Allergic medical history and family medical history Allergic medical history and family medical history is to be documented for patients with any occurrence of potential allergic reaction and will be coded according to the MedDRA dictionary (latest n in use at time of database lock). All details of allergic medical y and of allergic family medical history will be listed on an individual basis. 13.8.1.5 Pancreatitis Any cases of pancreatitis Will be documented as adverse events with detailed complementary information. A listing of individual data (separate from the listing of all adverse events) will be provided, sorted by patient, onset date and time, irrespective of the definition of the on—treatment phase, including notably description of the adverse event, values of amylase and lipase, gastroenterologist’s evaluation and potential causes of the pancreatitis. All cases will be described in detail in the clinical study report. 13.8.1.6 Hypoglycemia Symptomatic hypoglycemia will be reported together with all adverse events. 13.8.2 Clinical laboratory evaluations 13.8.2.1 Biochemistry, hematology and coagulation data Baseline definition The values to be used as baselines will be the values collected during screening assessments. If any of the scheduled ne tests are repeated for any patient, the last ked values will be considered as baselines, provided they were done before the first IMP administration and in the same conditions (e.g. fasting for glucose). alities analyses For parameters with laboratory ranges and/or abnormality criteria, an “on—treatment” analysis will be performed using all post-baseline ments done during the on—treatment phase, including all unplanned and rechecked values. Since laboratory assessments Will be performed during screening and at end-of—study visit (EOS), no on—treatment ements are pre—planned, only unscheduled values can occur during the on—treatment phase.

Data will be analyzed quantitatively using descriptive statistics, qualitatively by tabulating al abnormalities using Sponsor or tory criteria.

If appropriate, counts of patients With out—of—normal laboratory range values Will be provided in summary tables showing shifts from normal and abnormal baselines to post—baseline alities, presented by population and ent group. The same type of summary tables will be provided for out—of—normal laboratory range values. These tables are split by normal/abnormal status and missing value at baseline (if any).

Descriptive statistics and plots For ALT, AST, ALP, neutrophils, platelets and creatinine, e, lipase raw data and changes from baseline (percent change for creatinine) to EOS will be ized in ptive statistics, by population and treatment group.

Listings All individual data, for planned urinalysis, hematology and biochemistry, including rechecked values, will be listed by biological function. If any, data from unscheduled laboratory tests will also be listed. In these gs, individual data will be flagged when lower or higher than the lower or upper laboratory limits and/or when reaching the absolute limit of the Sponsor or tory criteria, when defined. A listing of out—of—normal range definitions will also be provided.

A listing of liver function data for patients experiencing at least one of the following situations will be provided as an in—text table: 0 ALT >3 ULN and total bilirubin > 2 ULN during the study, with at least one of them being post first dose, irrespective of the ion of the on~treatment phase 0 Conjugated bilirubin >35% of total bilirubin and total bilirubin >1.5 ULN, on the same sample post first dose, irrespective of the definition for the on—treatment phase.

If any, a listing d to increase in ALT 2 2 ULN will be provided, ing notably the information on IMP intake, medical and surgical history, alcohol habits, trigger factors, event details with ALT values, associated signs and symptoms. 13.8.2.2 Urinalysis All qualitative urinary test results (dipstick) and results fiom urinary pregnancy test, including rechecked values, will be listed. 13.8.3 Vital signs . 1 Blood pressure and heart rate Heart rate (HR) and systolic and lic blood pressure (SBP and DBP) will be analyzed as raw parameter value and change from ne (for supine position only), and as orthostatism parameter (standing—supine parameter values, when applicable).

The values to be used as baseline will be the pre—dose measurement on Day 1 of each period. If any of the scheduled baseline tests are repeated for any patient, the last ked values will be considered as ne, provided they were done before 1P administration.

Data will be analyzed quantitatively using descriptive statistics, qualitatively by tabulating clinical abnormalities using Sponsor or regulatory criteria.

For heart rate and blood pressures, raw data and changes from each baseline to EOS (for supine position only) will be ized in descriptive statistics, for each type of measurement and by population and treatment group. 13.8.3.2 Weight and body mass index The values to be used as nes will be the Day ~l value. Weight will be ed as raw parameter value and t change from baseline. Individual BMI will be calculated for any post—baseline weight assessment time point.

For weight, an “on—treatment” analysis will be performed using all post—baseline assessments done during the on—treatment period, including rechecked values Individual data for weight and BMI data will be listed. 13.8.4 Electrocardiogram ECG parameters obtained from automatic reading of lZ—lead ECG are used to support the safety analysis.

The values to be used as the baseline will be the Day 1 predose value of each period. If any of the scheduled baseline tests are repeated for any patient, the rechecked values will be considered as baselines, provided they were done before the first drug stration of the period.

HR, PR—, QRS—, QT, and corrected QT—interval (QTc) will be analyzed as raw parameter value and change from baseline to EOS.

Data will be analyzed quantitatively using descriptive statistics, qualitatively by tabulating clinical abnormalities using Sponsor or regulatory criteria. ":or all parameters, raw data and changes from baseline to EOS will be summarized in descriptive statistics, by population, parameter, population and treatment group. .ndividual data for all parameters, including rechecked values, will be .

Tn addition, patients with prolonged QTc (>450 ms) and/or change from baseline in QTc >60 ms will also be listed separately, using all ose timepoints.

A listing of ts with at least one abnormality in qualitative assessment (ie, abnormal ECG) after the 1st dosing will be also provided. 13.8.5 Other related safety parameters 13.8.5. 1 Anti-A VEOO1O dies t listing will be provided for anti—lixisenatide antibodies at baseline. If appropriate, frequency distributions will be provided. 13.9 ANALYSIS OF PHARMACOKINETIC DATA 13.9.1 Pharmacokinetic parameters The list of pharmacokinetics parameters is listed in Section 9.3.5. 13.9.2 Statistical is Pharmacokinetic ters of lixisenatide will be summarized by descriptive statistics (such as mean, geometric mean, median, standard deviation (SD), rd error of the mean (SEM), coefficient of variation (CV), (minimum, and m) by population and for each treatment under the sibility ofDrug Disposition, Safety and Animal Research, sanofi. Other statistical analyses described below will be performed under the responsibility of Biostatistics, sanofi.

The primary analysis will be based on the evaluable population.

Log— transformed lixisenatide pharmacokinetic parameters Cmax, AUClast, and AUC will be analyzed using a linear mixed effect model with fixed terms for treatment, sequence, period and a random term for a t—within~sequence. If the number of patients per sequence is too low the model might be adapted by excluding the sequence . - Estimates and 90% CI for the geometric mean ratio of 5 pg lixisenatide and versus 10ug lixisenatide will be ed by computing estimate and 90% CI for the difference between treatment means within the linear mixed effects model framework, and then converting to ratio by the antilog transformation to the original scale. 13.10 PHARMACOKINETICIPHARMACODYNAMIC ANALYSIS If appropriate, an explorative PK/PD analysis of lixisenatide concentrations vs pharrnacodynamics will be performed. 13.11 INTERIM ANALYSIS No interim analysis is planned 14 ETHICAL AND REGULATORY STANDARDS 14.1 ETHICAL PRINCIPLES This clinical trial will be conducted in accordance with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical Assemblies, and the ICH guidelines for Good Clinical Practice (GCP).

In compliance with sanofi~aventis public disclosure commitments, this al trial will be recorded on public registry web sites (eg, clinicaltrialsgov before the enrollment of the first patient). The registry will contain basic information about the trial sufficient to inform interested patients (and their healthcare practitioners) on how to enroll in the trial. 14.2 LAWS AND REGULATIONS This al trial will be conducted in accordance with all ational guidelines, national laws, and regulations of the country(ies) in which the al trial is performed, as well as any applicable guidelines for adults and paediatrics. 14.3 IN FORMED CONSENT The Investigator (according to applicable regulatory requirements), or a person designated by the Investigator and under the lnvestigator’s responsibility, should fully inform the patient of all ent s of the clinical trial including the written information giving approval/favorable opinion by the ethics committee ( RB/IEC) and Health Authorities (according to local regulations). All participants should be informed to the t extent possible about the study, in language and terms they are able to understand.

Prior to a t’s participation in the clinical trial, the written informed consent form should be signed, name filled in, and personally dated by the patient or by the patient’s legally acceptable representative, and by the person who ted the informed consent discussion. A copy of the signed and dated written informed t form will be provided to the patient.

For the children participation, local law must be ed in deciding whether one or both s/guardians consent is required. If only one parent or guardian signs the consent form, the Investigator must document the reason for only one parent or guardian’s signature.

In addition, participants will assent as detailed below or will follow the Ethics Committee (IRE/l *C) approved standard practice for pediatric participants at each participating center (age of assent to be determined by the lRB’s/IEC’s or be consistent with the local requirements): ipants who can read the Assent Form will do so before writing their name and dating or signing and dating the form.

Participants who can write but cannot read will have the assent form read to them before writing their name on the form. 14.4 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) As required by local regulation, the Investigator and/or the Sponsor must submit this al trial protocol to the riate lRB/IEC and Health Authorities (according to local regulations), and is required to forward to the respective other party a copy of the written "and dated approval/favorable opinion of the ethics committee (IRB/IEC) (signed by the chairman with IRE/EEC composition) and Health ities (according to local regulations).

The clinical trial (study number, clinical trial protocol title and version number), the documents reviewed (clinical trial ol, informed consent form, investigator’s brochure, Investigator’s curricula vitae, etc) and the date of the review should be clearly stated on the written IRB/IEC and Health Authorities (according to local regulations)approval/favorable opinion. igational medicinal product will not be released at the study site and the Investigator will not start the study before the written and dated approval/favorable opinion is/are received by the Investigator and the Sponsor.

During the clinical trial, any amendment or modification to the clinical trial protocol should be submitted to the RB/IEC and Health Authorities (according to local regulations)before implementation, unless the change is necessary to eliminate an immediate hazard to the patients, in which case the IRE/[EC should be ed as soon as possible. It should also be informed of any event likely to affect the safety of patients or the continued conduct of the clinical trial, in particular any change in safety. All s to the investigator’s brochure will be sent to the IRB/IEC.

A progress report is sent to the IRB/IEC and Health Authorities ding to local regulations)at least annually and a summary of the trial’s e at the end of the clinical trial.

BIBLIOGRAPHIC REFERENCES Investigator’s Brochure natide, Edition No. 8, 0 1 st April 2011 Centers for Disease Control and Prevention. National diabetes fact sheet United States, 2003: general information. Available at: http://WWW.cdc.gov/diabetes/pubs/factsheethtm. Accessed June 6, 2008.

Canadian Diabetes Association. Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008. Clinical Practice ines for the tion and ment of es in Canada. an Journal of Diabetes 2008:8161—8167. http://wvvw.diabetes.ca/files/cngOOS/cpg—2008.pdf Pinhas—Hamiel 0., Zeitler P. Clinical presentation and treatment of type 2 diabetes in children. Pediatric Diabetes 2007;8(9): 16—27 American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000; 23(3); 381-389.

[DP Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. Brussels: International Diabetes tion, 2005 Exenatide (marketed as Byetta) information; http:// .gov/cder/drug/infopage/exenatide/ defaulthtm Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ: Effect of metformin in ric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 25:89—94, Tanner JM, Davies, PS. Clinical longitudinal standards for height and height velocity for North American children. J r 1985;107(3):3l7~329.

. Tanner JM, Whitehouse RH, Takaishi M. Standards fiom birth to ty for height, weight, height velocity, and weight velocity: British children, 1965. II. Arch Dis Child. 1966;4l(220):613—635 ll. r TMS, Jenkins D. JA, Ocana A.M, Rao VA, Collier G.C. Second—meal effect: low- glycemic —index foods eaten at dinner improve subsequent breakfast glycemic response. Am J CLin Nutr 1988;48:1041-7. 12. Nilsson A, Ostman E, Preston T and Bjorck. Effects of Gi vs content of cereal fibre of the evening meal on glucose tolearance at a subsequent standardized breakfast. Eur. J Clin Nutr.2008 62, 712-720.

The body mass index (BMI) for age percentiles by gender is shown in Figures 3-4, also referred to as Appendix A. Figure 3 shows the body mass for—age percentiles for boys from 2 to 20 years. Figure 4 shows the body mass index-for-age percentiles for girls from 2 to 20 years.

Appendix B Blood pressure levels by gender, age and height percentile 90m Percentile 01 Blood Pressure in Boy: 2 to 17 Years of Age According to Height Percentile 600% Systolic BP for Height tile of: 90'1“!» 011110111: BP tor Hal ontlla of: Age 5!! 251'I 50"I 751* 95" 51'1 26"1 W 751" 95" ' "‘ ‘ 2 98 100 102 104 105 55 56 57 53 59 4 102 105 107 109 110 62 63 64 65 66 6 105 108 110 111 113 2 67 69 70 70 71 8 107" 110 112 114 115 71 72 73 74 75 110 113 115 117 118 73 74 75 76 77 7 ' W 77 12 115 117 119 121 123 75' 76 77 78W 78 " " 78 "" 14 120 123125126 128.1 76' 77 79 "86‘” 16 12.5 128 1.30; 133 79 so 81 32 33 _ 132 1 17 128 131 133 134 136 81 112 as 114 85 90"1 Percentile of Blood Pressure in Girls 2 to 17 Years of Age According to Height Percentile Age 5'" 259' 50'“ 757' 95“ 91* 26" 5011' 75"! 9511' 2 99 100 102 103 104 57 58 56 59 60 '4 161 103 104 106 107 63 64 65 65 66 6 104 1W16 107 109 110 67 66 69 69 70 ' "TV"'1__71'1__'f_”7§'1 8 100 110 111 11112 __. 1113' "1' “70' 173“ 1 ' " ‘75 W6 112 114 115""'_””'1'1”6'“ '11"? ‘73 73 "74' 12 116 118' 119 120 121 75 76 76 77 78 14 119 121 122 121 125 77 78 80 1 1 79 1 117911 “16‘ 122 123 125 126 127 79 79 so 81 82 17 1221 121 1 11125 126 128 79 79 30 a1 82 Appendix C Calculation of Creatinine-Clea‘rance by Cockroft and Gault Male: Creatinine clearance[mL/min] = 1140 — age lyearsl) x weight [kg] creatinine [mg/dL] X 72 Female: Creatlnme clearance[mL/min] ——.. . _(”0 _ age D!emD xwe‘‘§3[]_5tk° XOS nine [mg/dL] x 72 RECTIFIED SHEET (RULE 91) ISA/EP Appendix D: Meal test (standardized breakfast) Ensure Plus Next Generation Vanilla List of ingredients in descending order: Water, maltodextrin, hydrolized corn starch, sucrose, milk protein isolate, canola oil,CASElNATES (calcium caseinate, sodium caseinate), corn oil, MINERALS m citrate, potassium citrate, magnesium chloride, potassium chloride, magnesium phosphate dibasic, calcium phosphate tribasic, potassium phosphate dibasic, ferrous sulfate, zinc sulfate, manganese sulfate, cupric sulfate, sodium molybdate, ium iodide, chromium chloride, sodium selenate), ascorbic acid, soy protein e, flavoring, soy lecithin, cellulose, NS (choline chloride, dl—alpha tocopheryl acetate, niacinarnide, calcium pantothenate, xine hydrochloride, thiamine hydrochloride, riboflavin, Vitamin A palmitate, beta carotene, folic acid, phylloquinone, , Vitamin D3, eyanocobalamin), sodium carboxymethyl cellulose, gellan gum.

May contain: sodium chloride.

Approximate analysis Energy EU kcal Keal 300 Energy EU id 1263 LProtein g 12.50 Fat 9 9.84 Carbohydrate g 40.40 Water 9 154.86 ”— ‘7 VITAMINS, .

Vitamin A (palmitate) meg RE 175 Vitamin A (palmitate) [U 584 Vitamin A (B—caretene) meg RE 58 Vitamin A otene) lU 584 Vitamin D3 meg 4.0 Vitamin D3 IU 160 Vitamin E iU 6.4 Vitamin K1 meg 24 Vitamin C mg 24 Folic acid meg 80 Vitamin B1 mg 0.40 Vitamin Bz mg 0.54 Vitamin Be mg 0.54 n B12 meg 1.1 Niacin lent 5.2 . mg Panthothenie acid mg 2.2 Biotin meg 12 Choline mg 110 MINERALS“ ' Sodium mg 184 Potassium mg 320 Chloride mg 220 Calcium mg 120 orus mg 200 Magnesium mg 60 Iron mg 4.2 Zinc mg 3.6 Manganese mg 1.0 Copper mcg 360 Iodine mcg 44 Selenium mcg 17 Chromium mcg 15 Molybdenum mcg 32 Example 2 A randomized, -blind, placebo controlled trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of lixisenatide in paediatric (10-17 years old) and adult patients with type 2 diabetes Sponsor] Company: Sanofl Drug substance(s): Lixisenatide (AVEOOiO) Title of the study: A randomized, double—blind, placebo controlled trial to assess safety, tolerability, cokinetics and pharmacodynamics of lixisenatide in paediatric (10~17 years old) and adult patients with type 2 es Study center(s): Six centers from 4 countries (pediatric patients from 4 centers in Mexico, South Africa, and the United States [US] and adult patients from 2centers in the US and United Kingdom) ' Study period: Date first patient enrolled: 24/May/2012 Date last patient completed: 04/Mar/2014 Phase of development: Phase 1 Objectives: Primary objective: 0 To investigate the effects of a single aneous (SC) lixisenatide dose of 5 pg and 10 pg as compared to placebo in reducing postprandial plasma glucose (PPG) assessed as area under the plasma glucose concentration curve after a standardized liquid meal (breakfast) in type 2 ic pediatric population (10-17 years old) and adults as controls.

Secondary ives: To te in both pediatric and adult populations: . Pharmacokinetic (PK) parameters of lixisenatide in plasma after single SC ascending doses. 9 The maximum PPG excursion, and the changes in n, C-peptide, and glucagon plasma trations following a standardized breakfast. a Safety and tolerability Methodology: Multicenter, double-blind, randomized, o—controlled, single-dose, 3-period, 34treatment, 6-sequence crossover study in pediatric and adult patients with type 2 diabetes mellitus (TZDM) Number of patients: Planned: 12 pediatric patients/12 adult patients Randomized: 12 pediatric patients/13 adult patients Treated: 12 pediatric patients/12 adult ts Evaluated: Overview of study populations Pediatric patients Adult patients Number of patients for: Evaluable codynamics population (N) 9a 12 Full analysis pharmacodynamics population (N) 12 12 Evaluable cokinetics population (N) 81) 10b Full is pharmacokinetics population (N) 12 12 Safety population (N) 12 12 a Three patients ed: 2 patients had vomiting within 4 hours after the rdized meal test and 1 patient ingested only half of the standardized meal test. b Four pediatric and 2 adult patients excluded: lixisenatide plasma concentrations below lower limit of quantification (LLOQ) in all samples in at least one period or no more than 3 consecutive samples above LLOQ in at least 1 period.

Diagnosis and ia for inclusion: Male and female patients with T2DM, with or without metformln (at a stable dose for at least 4 weeks prior to randomization); HbA1c27% and 310% at screening; fasting C—peptide >O.6 ng/mL at screening; negative test for nsulinoma-associated protein and anti—glutamic acid decarboxylase autoantibodies.

Pediatric population: Male and female patients 210 and <18 years of age with at least 3 patients below 15 years of age and no more than 3 patients 216 and <18 years of age, body mass index (BMI) >85th percentile for age and gender, and BMI $50 kg/m2 (body weight >50 kg) Adult population: Male and female patients 218 and 565 years of age, and with BMI >25 kg/m2 and $37 kg/mZ.

Study treatments igational medicinal product(s): Lixisenatide and placebo Formulation: Lixisenatide (100 pg/mL) and placebo, provided as ons for injection in a 3-mL glass cartridge Route(s) of administration: SC injection with pen-type injector lik®) Dose regimen: In each of the 3 treatment periods, patients were administered, in fasted conditions, a single dose of 5 pg lixisenatide or 10 pg lixisenatide (with 5 pg ing the 10 pg dose level) or placebo (50 or 100 pL), 30 minutes before a standardized liquid breakfast.

Duration of treatment: Three treatment periods, each lasting 1 day (up to 2 days in case of institutionalization on the evening of Day -1).

Duration of observation: Up to 7 weeks for each patient including a screening period of up to 28 days, 3 treatment periods of up to 2 days ted each by a washout period of 1 to 7 days and an endofstudy visit 1 to 6 days after the last investigational medicinal product (IMP) administration.

Criteria for evaluation: Pharmacodynamics: Primary endpoint: 0 Plasma glucose: corrected plasma glucose-AUCoaomsom area under the curve for plasma glucose concentration-time profile calculated from time of standardized breakfast start (30 minutes after IMP injection and premeal plasma glucose=TOH30) until 4 hours later (T4H30) after subtracting the premeal value ) Secondary endpoints: . cursiono;soh-4;aoh: m change in PPG from time of standardized breakfast start (30 minutes after IMP injection=TOH30) until 4 hours later (T4H30) . AUCOZ30h—4I30h of plasma glucose, n, C-peptide, and glucagon: area under the curve for plasma glucose, insulin, C-peptide or glucagon concentration-time profiles from time of standardized breakfast start (30 minutes after IMP ion=TOH30) until 4 hours later (T4H30) Safety: Patients were monitored for safety via adverse events (AEs) reported by the patient or noted by the Investigator, physical ation, body temperature, standard clinical laboratory evaluations, vital signs, and electrocardiogram (ECG) ters.

Pharmacokinetics: Lixisenatide plasma tration, PK parameters um plasma concentration observed [Cmax], time to reach Cmax , area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to the real time [AUCIast], area under the plasma concentration versus time curve extrapolated to infinity [AUG], area under the plasma concentration versus time calculated using the trapezoidal method from time TOH30 to T4H30 [AUCOz30h-4230h1).

PharmacokineticIPharmacodynamic sampling times and bioanalyticai methods: Blood s for pharmacodynamic (PD) analysis were collected at each treatment period for plasma glucose, glucagon, insulin and C-peptide assessments: blood samples were taken 30 minutes before a standardized breakfast and prior to dosing (T0), then immediately prior to the standardized breakfast (TOH30 hours), and thereafter at T1, T1 H30, T2, T2H30, T3H30, and T4H30 (ie, , 60, 90, 120, 180, and 240 s eakfast) for AUCO:30h-4:30h for plasma glucose, glucagon, insulin, and C-peptide measurements.

The quantitative is of plasma glucose was assessed using the GIuco-quant GIucose/hexokinase assay for glucose from Roche Diagnostics, Mannheim, Germany. The range of the method was 3—1000 mg/dL, with i mg/dL as limit of detection (LOD), 3 mg/dL as lower limit of fication (LLOQ), and 1000 mg/dL as upper limit of quantification.

The method for quantitative analysis for human C~peptide was assessed using the Electro Chemiluminescence Immuno Assay (ECLIA) from Roche Diagnostics, Mannheim, Germany. The range of the method was 0.2-25 ng/mL, with an LLOQ of 0.2 ng/mL and an LOD of 0.07 ng/mL.

The method for quantitative analysis of glucagon was assessed using the radioimmunoassay (RlA) from Euro-Diagnostica, Malmd, Sweden. The range of the method was 4.7—150 pmoI/L.

The method for tative analysis of insulin was assessed using the ECLlA assay from Roche Diagnostics Deutschland GmbH, im, Germany. The range of the method was 1—875 mIU/L, with an LLOQ of 1 mIU/L and an LOD of 0.3 mIU/L.

Blood samples for PK analysis were collected at each treatment period for the determination of lixisenatide plasma concentrations: blood samples were taken 30 s before a standardized breakfast and prior to dosing (T0), and thereafter at TOH30, T1, T1 H30, T2H30, T3H30, T4H30, and T6H30.

Lixisenatide plasma concentrations were determined using a validated double—antibody sandwich enzyme-linked immunosorbent assay method with an LLOQ of 5.5 pg/mL.

Anti-lixisenatide antibody status and, if positive, anti-lixisenatide antibody concentrations were determined using the validated BlAcore technique with a study-specific, and thus not prospectively determined, cutoff as LLOQ. Blood samples were taken only on Day 1/Period 1 before the first IMP administration.

Statistical methods: Pediatric and adult patients were analyzed separately. Results were compared between the 2 populations descriptively.

Pharmacodynamics: Within each crossover, the analyses of the primary PD endpoint were performed based on the ble PD population, using the full analysis PD population as supportive analyses. Corrected plasma glucose —tacit was analyzed using a linear mixed-effect model with sequence, period, and treatment effect as fixed effects, and patient within sequence as random effect, and the TOHBO plasma glucose concentration as covariate. The least square (LS) mean differences between treatment groups and the corresponding 95% confidence intervals (Cls) were estimated within the linear mixed model framework. A cance level of p<0.05 was used.

Secondary PD parameters were analyzed using the same statistical model as described above with the corresponding TOHSO values as covariates.

Pharmacokinetics: The statistical analyses of PK ters were done on the evaluable PK population, using the full analysis PK population as supportive analyses.

Log-transformed natide PK parameters Cmax, t. and 0h-4;30h were analyzed using a linear mixed-effect model with fixed terms for sequence, treatment and a random term for a t-within-sequence. Estimates and 90% Cls for the geometric mean ratio of lixisenatide 10 pg versus lixisenatide 5 ug were ed by ing estimate and 90% Cls for the difference between treatment means within the linear mixed-effects model framework, and then converting to ratio by the antilog transformation to the original scale.

Safety: The safety analysis 'was based on the review of the individual values (clinically significant abnormalities) and descriptive statistics (summary tables and plots if appropriate) by treatment.

Treatment—emergent adverse events (TEAEs) classified in system organ classes (8003) and red terms were summarized by number and percentage of patients and number of TEAEs. individual clinical laboratory data, vital signs, and ECGrdata were listed and flagged for potentially clinically significant abnormalities (PCSAs) and for lower and upper clinical laboratory limits.

Frequency of patients with abnormalities and with on-treatment PCSAs were summarized for each type of parameter by treatment.

Population characteristics: Twelve pediatric and 12 adult patients with T2DM were randomized and treated. One additional adult patient was randomized but not treated (this t withdrew from the study due to al reasons before the first IMP administration). All patients were on concomitant metformin therapy during the study.

Demographics and baseline characteristics for ric and adult ts are summarized in the table below.

Demographics, patient, and disease characteristics at baseline in pediatric and adult patients, safety population Pediatric patients Adult patients N 12 12 Mean age (years) [min~max] 13.9 [10—17] 51.3 [41—60] Age group (years) (n, %) [10—15] 7 (58.3%) [15—16] 2 (16.7%) 3 (25.0%) [18-50] 5 (41.7%) [50—65] 7 (58.3%) Sex (n [%]) Male 6 (50%) 9 (75%) Female 6 (50%) 3 (25%) Race (n [%]) Caucasian/white 1 (8.3%) 6 (50%) Asian/oriental 1 (8.3%) Othera 11 (91.7%) 5 (41.7%) Mean weight (kg) ax] 84.69 [560-1290] 92.58 [747-1353] Mean BMl (kg/m2) [min-max] 31.42 [22.7-44.1] 31.79 [27.0-36.1] Duration of diabetes (years): 1.56 [05-79) 4.45 [1 9-20.41 median [min-max] Duration of metformin treatment (years): 1.56 [0.5-7.6] 2.13 [0.4-7.4] median [min-max] Mean HbA1c (%) [min—max] 8.65 [7.09.9] 8.43 [7.2-9.1] Among 11 pediatric patients, 7 self-reported as Hispanic and 4 self—reported as a group of mixed race in South Africa (the Cape d). Five adult patients self—reported as Hispanic or Latino.

Pharmacodynamic results: Primary pharmacodynamic endpoints: in the pediatric evaluable PD population, the corrected plasma glUCOSG-AU00130h-4230h was decreased by single doses of lixisenatide 5 and 10 pg compared to placebo, but the differences versus placebo were not statistically significant. For the primary endpoint (corrected plasma glUCOSe'AUCO:30hA:30h), the LS mean difference between the lixisenatide 5 pg dose and placebo was -3.92 mmolh/L; 95% Cl: -8.17 to 0.34 mmol.h/L, p=0.0681 (-70.56 mg.h/dL; 95% Cl: -147.15 to 6.04 mg.h/dL).

The L8 mean difference between natide 10 pg and placebo was -1.52 mmol.h/L; 95% Cl: -5.59 to 2.56 mmol.h/L, p=0.4359 (27.33 L; 95% Cl: -100.75 to 46.10 mg.h/dL) (see tables below).

Pediatric patients - plasma glucose premeal corrected AUC0230h-4230h (mmol.hlL) per treatment group and difference of lixisenatide 5 pg and 10 pg to placebo - evaluable PD population Least Square Means (SE)a Treatment N Corrected plasma Corrected plasma 95% Cl of p-value group glucose-AUCo:304:aoh giucose-AUCmomon ence [mmol.h/L] difference to placebo [mmol.h/L] [mmol.h/L] o 9 9.63 (3.95) Lixisenatide 9 5.72 (3.99) -3.92 (1.97) (-8.17; 0.34) 0.0681 Lixisenatide 9 8.11 (4.08) -1.52 (1.89) 0.4359 . (5.59; 2.56) pg a SE (standard error) ric patients - plasma glucose premeal corrected 0h-4:30h (mg.hIdL) per treatment group and difference of lixisenatide 5 pg and 10 pg to placebo = ble PD population Least Square Means (SE)a Treatment N ted plasma Corrected plasma 95% CI of p-value group giucose-AUCo;3o4;aoh glucose-AUCo;ao4:soh difference [mg.h/dL] difference to placebo [mg.h/dL] Placebo 9 173.51 (71.24) Lixisenatide 9 102.96 (71.81) -70.56 (35.46) (147.15; 6.04) 0.0681 Lixisenatide 9 146.19 (73.44) -27.33 (34.00) (-100.75; 0.4359 pg 46.10) 8 SE (standard error) In contrast to pediatric patients, in the adult ble PD population, single doses of lixisenatide 5 and 10 pg significantly reduced PPG assessed as ted plasma e-AUCoaomson compared to placebo. The L8 mean ence between lixisenatide 5 pg dose and placebo was -8.57 mmolh/L; 95% Cl: -14.91 to -2.23 mmol.h/L, p=0.0104 (~154.41 mg.h/dL; 95% CI: 26.860 to 4.0 21 mg. h/dL). The L8 mean difference n lixisenatide 10 pg and placebo was--15.48 mmol. h/L; 95% Cl: -21. 59 to -.938 mmol. h/L, p<0.0001 (—2.7893 mg.h/dL; 95% CI: -388.96 to 1.68 90 mg.h/dL) (see tables below). The difference between lixisenatide 10 and 5 pg was not statistically significant.

Adult patients - plasma glucose premeai corrected AUCOz30h-4z30h (mmol.hIL) per treatment group and difference of Iixisenatide 5 pg and 10 pg to placebo - evaluable PD population Least Square Means (SE)a Treatment N Corrected plasma Corrected plasma 95% CI of p-value group glucose-AUC02304:30h giUCOSB-AUCo:30-4:30h difference [mmol.h/L] difference to placebo [mmol.h/L] [mmol.h/L] Placebo 12 16.60 (2.46) Lixisenatide 12 8.03 (2.95) -8.57 (3.05) (14.91 ;-2.23) 0.0104 Lixisenatide 12 1.11 (2.85) ~15.48 (2.93) (21.59 ; -9.38) <0.0001 pg a SE (standard error) Adult patients - plasma glucose premeai ted AUCO:30h-4:30h (mg.hldL) per treatment group and difference of Iixisenatide 5 pg and 10 pg to placebo - evaluable PD population Least Square Means (SE)a Treatment N » Corrected plasma Corrected plasma 95% CI of p-value group e-AUCo;3o.4:auh glucose-AUCo;304;3oh difference [mgh/dL] difference to o [mg.h/dL] [mg.h/dl_] Placebo 12 299.01 (44.36) Lixisenatide 12 144.60 (53.18) ~154.41 ) (268.60 ; -40.21) 0.0104 119 Lixisenatide 12 20.08 (51.37) -278.93 (52.81) (388.96 ; -168.90) <0.0001 pg a SE (standard error) Secondary phannacodynamic endpoints: in the pediatric ble PD population, the results for plasma glucose AUCo:aon4;30h were consistent with those for the primary endpoint (corrected plasma giucose-AUCaaameon). Single dose of Iixisenatide 5 pg significantly reduced the m PPG excursion ed to placebo: the LS mean difference n Iixisenatide 5 pg and o was —1.50 mmol/L; 95% Cl: —2.94 to -0.07 mmol/L, p=0.0415'(-27.08 mg/dL; 95% CI: -52.95 to -1.22 . The ence between lixisenatide 10 pg and placebo was not statistically significant: the LS mean difference was -1.13 mmol/L; 95% CI: —2.50 to 0.25 mmol/L, p=0.1005 (20.30 mg/dL; 95% Cl: -45.09 to 4.50 mg/dL).

In the pediatric ble PD population, the AUCO;30h-4:30h for glucagon, n, and C-peptide were decreased with both lixisenatide 5 and 10 pg compared to placebo except for insulin that increased with Iixisenatide 5 pg; r, the variability was high (see tables below). The differences between lixisenatide 5 or 10 pg and placebo were not statistically significant for any of these endpoints, except the decrease in glucagon with lixisenatide 10 pg. No statistically significant ences between lixisenatide doses were observed for any ary endpoint in the pediatric evaluable PD population.

In the adult evaluable PD population, the results for plasma glucose AU00130h-4130h were consistent with those for the y endpoint (corrected plasma giUCOSe‘AUC0230h4:30h). Single doses of Iixisenatide 5 and 10 pg significantly reduced the maximum PPG excursion during the postprandial period up to 4 hours after the standardized breakfast, compared to placebo. The L8 mean difference between Iixisenatide 5 pg and placebo was -2.78 mmol/L; 95% Cl: 4.29 to -1.27 mmol/L, p=0.0010 (-50.06 mg/dL; 95% Cl: -77.27 to 22% mg/dL), and the LS mean difference between lixisenatide 10 pg and placebo was -4.32 mmoi/L; 95% CI: -5.77 to -2.87 mmol/L, p<0.0001 (-77.85 mg/dL; 95% CI: 403.95 to -51.76 mg/dL).

In the adult evaluable PD population, the AUC0230h—4230h for glucagon, insulin, and ide were decreased with both atide and 10 pg compared to placebo, and these decreases were statistically significant with natide 10 pg (see table below). The decreases in AUCo;30h4:30h for glucagon and C-peptide were not statistically significantly different between lixisenatide doses. The decrease in AUCosouoaon for insulin with lixisenatide 10 pg compared to lixisenatide 5 pg was statistically significant: the LS mean difference was -378.97 /L; 95% Cl: -711.56 to 46.38 pmolh/L, p=0.0277 (63.16 mclU.h/mL; 95% Cl: —118.59 to -7.73 mcth/mL).

Pediatric patients - AUCO:30h-4:30h for plasma glucose, glucagon, insulin, and C-peptide per ent group and difference between lixisenatide 5 and 10 pg to placebo (SI units) — evaluable PD population Least Square Means (SE)a Parameter Treatment group N AUCo;3o-4;30h Difference to 95% CI of p-value o ence Plasma glucose Placebo 9 44.50 (3.91) (mmol.h/L) Lixisenatide 5 pg 9 40.53 (3.94) -3.97 (1.93) (8.13 ; 0.19) 0.0599 Lixisenatide 10 pg 9 42.94 (4.03) -1.56 (1.85) (5.55 ; 2.43) 0.4147 Glucagon Placebo 9 664.83 ) (ng.h/L) Lixisenatide 5 pg 8 652.63 (22.22) ~12.20 ) (58.05 ,' 33.65) 0.5769 Lixisenatide 10 pg 9 621.48 (20.77) 43.35 (18.30) (83.25 ;—3.45) 0.0356 insulin Placebo 7 1843.81 (297.88) (pmo|.h/L) Lixisenatide 5 pg 8 1973.88 (243.52) 130.07 (372.42) (668.69 ; 928.83) 0.7321 Lixisenatide 10 pg 8 1602.80 (239.93) -241.01 (365.37) (1024.64 ,' 0.5202 ' 542.63) C—peptide Placebo 8 9.92 (0.56) (nmol.h/L) Lixisenatide 5 pg 8 9.87 (0.59) 004 (0.80) (1.79 ;1.71) 0.9565 Lixisenatide 10 pg 8 9.21 (0.58) —0.70 (0.74) (2.35 ; 0.94) 0.3631 a SE (standard error) Pediatric patients - AUCO:30h-4:30h for plasma e, glucagon, insulin, and ide per treatment group and difference between Iixisenatide 5 and 10 pg to placebo (US units) ~ evaluable PD tion Least Square Means (SE)a Parameter Treatment group N AUCO:30-4:30h Difference to 95% CI of p-value placebo difference Plasma glucose Placebo 9 “ 801.63 (70.40) (mgh/dL) Lixisenatide 5 pg 9 730.11 (70.95) —71.52 (34.71) (146.51; 3.47) 0.0600 natide 10 pg 9 773.58 (72.53) —28.04 (33.29) (99.92; 43.84) 0.4147 Glucagon Placebo 9 664.83 (19.92) (pg.h/mL) Lixisenatide 5 pg 8 652.63 (22.22) -12.20 (21.35) (58.05; 33.65) 0.5769 Lixisenatide 10 pg 9 621.48 (20.77) 43.35 (18.30) (83.25; ~3.45) 0.0356 Insulin Placebo 7 307.30 (49.65) h/mL) Lixisenatide 5 pg 8 328.98 (40.59) 21.68 (62.07) (111.45; 154.80) 0.7321 Lixisenatide 10 pg 8 267.13 (39.99) 40.17 ) (170.77; 0.5202 90.44) C—peptide Placebo 8 29.78 (1.69) (ng.h/mL) Lixisenatide 5 pg 8 29.65 (1.76) -0.13 (2.41) (5.39; 5.12) 0.9565 Lixisenatide 10 pg 8 27.67 (1.76) -2.11 (2.22) (7.05; 2.82) 0.3631 8 SE (standard error) Adult patients - AUC0130h-4:30h for plasma e, glucagon, insulin, and ide per treatment group and difference between lixisenatide 5 and 10 pg to placebo (Si units) - evaluable PD population Least Square Means (SE)a Parameter Treatment group N AUCO:30-4:30h . Difference to 95% CI of p-value placebo difference Plasma P acebo 12 54.32 (2.46) glucose (mmol.h/L) L'xisenatlde 5 pg 12 45.75 (2.95) 857 (3.05) (14.91; -2.23) 0.0104 natide 10 pg 12 38.83 (2.85) —15.48 (2.93) (21.59; 9.38) <0.0001 Glucagon P acebo 12 628.98 (26.47) (ng.h/L) L‘xisenatide 5 pg 12 612.44 (27.90) 46.54 (18.48) (55.53; 22.46) 0.3834 L'xisenatide 10 pg 12 575.30 (27.95) 63.68 (18.59) (92.89; . 0.0102 44.46) Insulin P acebo 12 1276.36 (85.63) (pmolh/L) L'xisenatide 5 pg 11 1181.62 —94.74 (124.99) (356.57; ) 0.4579 (103.75) Lixisenatide 10 pg 12 802.65 (104.20) 473.71 (126.74) (738.96; 0.0014 ' ’”' 208.45) C—peptlde P acebo 12 8.90 (0.48) (nmol.h/L) natide 5 pg 11 8.42 (0.56) -0.47 (0.64) (1.81; 0.87) 0.4701 Lixisenatide 10 pg 12 6.81 (0.56) —2.09 (0.63) (3.40; 017) 0.0036 a SE (standard error) Adult patients - AUCO:30h-4:30h for plasma glucose, glucagon, insulin, and C-peptide per treatment group and difference between lixisenatide 5 and 10 pg to placebo (US units) - evaluable PD tion Least Square Means (SE)3 Parameter Treatment group N 0-4:30h Difference t0 95% CI of p-value placebo difference Plasma Placebo 12 978.50 (44.36 glucose (mg.h/dL) Lixisenatide 5 pg 12 824.10 (53.18 ~154.41 (54.99) (268.60 ; 0.0104 . 40.21) Lixisenatide 10 pg 12 699.58 (51.37 -278.93 (52.81) (388.96 ; <0.0001 -168.90) on Placebo 12 628.98 (26.47 (pg-h/mL) leisenatide 5 pg 12 612.44 (27.90) -16.54 (18.48) (55.53 ; 22.46) 0.3834 Lixisenatide 10 pg 12 575.30 (27.95 -53.68 (18.59) (92.89 ; 0.0102 44.46) insulin Placebo 12 212.73 (14.27 (mclU.h/mL) Lixisenaiide 5 pg 11 196.94 (17.29) -15.79 ) (59.43 ; 27.85) 0.4579 Lixisenatide 10 pg 12 133.77 (17.37 -78.95 (21.12) (123.16 ; 0.0014 ~34.74) ~ C—peptide Placebo 12 26.71 (1.45) mL) leisenatlde 5 pg 11 25.30 (1.69) -1.42 (1.92) (5.43 ; 2.60) 0.4701 118881818810 12. - -1 188 .. . , . ., . a SE (standard error) Pharmacokinetic results: natide plasma trations were below LLOQ in all samples from 2 pediatric patients treated with lixisenatide 10 pg and 1 adult patient treated with lixisenatide 5 pg. For 1 pediatric and 1 adult patient treated with lixisenatide 5 pg and 1 pediatric patient treated with lixisenatide 10 pg, no more than 3 consecutive samples were above LLOQ and ore these patients were not evaluable for PK analysis. ln the pediatric evaluable PK population, the exposure of lixisenatide was similar for both dose groups. A high variability was ed with lixisenatide 10 pg. For Cmax, the ient of variation (CV%) was 47.7% for lixisenatide 5 pg and 74.3% for lixisenatide 10 pg. For AUClast, the CV% was 78.2% for natide 5 pg and 101.1% for lixisenatide 10 pg. in the pediatric evaluable PK population, the point estimate of the treatment ratio (lixisenatide 10 pg versus lixisenatide 5 pg)'for Cmax was 1.04 (90% Cl: 0.71 to 1.51) and for AUClast was 0.88 (90% Cl: 0.51 to 1.49).

In the pediatric full PK population, the exposure was slightly higher in patients treated with lixisenatide 10 pg compared to treatment with lixisenatide 5 pg. A high variability was observed for both dose . For Cmax, the coefficient of variation (CV%) was 51.7 for natide 5 pg and 72.1 for lixisenatide 10 pg. For AUClast, the CV% was 92.5 for lixisenatide 5 pg and 97.4 natide 10 pg. ' Following single-dose SC administration in adult patients, the exposure of lixisenatide increased with the dose, and was tional with dose for the evaluable and full PK population.

In pediatric patients, the exposure was similar to that in adults treated with lixisenatide 5 pg, but lower than in adults treated with ‘ lixisenatide10 cokinetic parameters for lixisenatide in plasma - evaluable PK populations Plasma Lixisenatide Mean i SD Paediatric Adults (Geometric Mean) [CV%] ‘ natide 5 pg Lixisenatide 10 pg Lixisenatide 5 pg Lixisenatide 10 pg N 8 8 10 10 Cmax 29.7 i 14.2 34.3 i 25.4 26.0 i 15.4 55.9 i 21.3 (pg/mL) (26.3) [47.7] (27.2) [74.3] (22.8) [59.4] (53.3) [37.5] tmaxa 1.25 0.49 1.50 2.50 (h) (0.48 - 3.50) (0.48 — 3.55) (0.42-3.50) (0.42 - 3.50) 11/22 3.19 i 1.12 2.52 i 0.775 3.10 i 1.22 2.79 i 1.35 (h) (3.01) [35.1]b (2.41) [30.8]c (2.89) [39.3] (2.59) [48.1] AUClast 99.4 i 77.7 108 i 109 101 i 58.0 242 i 90.0 (pg-h/mL) (76.9) [78.2] (67.4) [101.1] (90.8) [57.3] ' (228) [37.2] AUCO:30h-4:30h 82.5 i 54.6 88.0 i 76.0 77.2 i 42.4 181 i 71.9 (pg~h/mL) (67.4) [662]” (64.3) [86.4]c (70.0) [54.9] (168) [39.6] 3 Median (Min - Max) evaluable paediatric population ts: 484001004 - 006, 484001008, 484001010, 710002001, 710002005, 710002009 b N: 7 for subject 710002005 missing could not be calculated ° N: 7 for subject 710002009 missing could not be calculated evaluable adult population: subjects 826001004, 826001021, 840005006, 010011, 840005014, 840005016 - 017, 840005020-021 Source = PKS Study : PKD11475; Scenario: P-D—A-EV—OD, Version 1, P-D-A~EV-OD-E02, Version 3 Point estimates of ent ratios of Iixisenatide 10 ug versus 5 ug — evaluable PK population Point estimate ratio [90% Cl] Pediatric Adults N 8 10 Cmax 1.04 2.34 . [0.71 — 1.51] [1.85—2.95] AUCIast 088 2.51 [0.51 — 1.49] [1.90 — 3.30] AUCo:30.4:30n 0.93 2.41 [0.57 —1.50] [1.88 — 3.08] Safety results: No serious AEs were ed during the study, and no patient discontinued the study due to TEAEs. in the pediatric population, 4 patients (1 after injection of placebo, 1 after lixisenatide 5 pg, and 2 after lixisenatide 10 pg) experienced 6 TEAEs (5 from the gastrointestinal disorders SOC and 1 from the infections and infestations SOC). Of these ts, 1 experienced vomiting of mild intensity 43 minutes after injection of placebo (5 minutes after the rdized liquid breakfast), and another patient enced vomiting of mild intensity with concomitant nausea 3 hours and 15 minutes after injection of lixisenatide 5 pg (2 hours and 31 minutes after the standardized liquid breakfast). One patient experienced diarrhea and concomitant nausea after injection of natide 10 pg. The incidence of TEAEs was low in the adult population (1 event of diarrhea in 1 placebo—treated patient). All TEAEs were of mild to moderate intensity. All patients red without sequelae with or without corrective treatment.

In the pediatric population, there were few PCSAs for blood pressure with no relationship to the IMP or dose administered. Few patients had PCSAs for ECG parameters (prolonged PR, QRS, and QTC) without relevant ences between lixisenatide and placebo. - There were no PCSAs (during the on—treatment period) for blood pressure or ECG parameters in the adult population.

All patients, except 1 adult, were anti'lixisenatide antibody negative at study entry.

Conclusions: After a rdized liquid ast in 12 pediatric patients with T2DM aged between 10 and less than 18 years old, with a mean HbA1c of 8.65% and mean body weight of 84.7 kg treated with metformin as a background therapy, a non-significant decrease in plasma glucose (corrected plasma glucose AUC0:30h-4230h and plasma e AU Comment) was observed with single doses of natide 5 and 10 pg compared to placebo. in st, single doses of lixisenatide 5 and 10 pg significantly reduced plasma glucose (corrected plasma glucose AUCUIEOh-4230h and plasma glucose AUCO:30h~4:30h) in 12 adult patients with T2DM compared to placebo. This PPG-lowering effect in adult patients treated with lixisenatide 10 pg was associated over the same period with statistically significant decreases in concentrations of glucagon, insulin, and C-peptide. These PD s occurred to a lesser extent with lixisenatide 5 pg. in pediatric patients, 0h—4:30h for glucagon and C-peptide were decreased with lixisenatide 5 and pg compared to placebo, and the effects were more marked with lixisenatide 10 pg (p=0.04 for glucagon decrease). Of note, a large variability was observed mainly for 0h-4:30h for insulin, which increased with lixisenatide 5 pg and decreased with lixisenatide 10 pg.

Following single subcutaneous administration, lixisenatide exposure was similar for both dose groups in the evaluable pediatric patients, whereas in adult patients, the lixisenatide exposure dose-proportionally increased. In the full ric PK population, lixisenatide exposure was slightly higher for the higher dose of 10 pg. ln pediatric patients, the re was similar to that in adults for lixisenatide 5 pg, but lower for lixisenatide 10 pg.

Single doses of lixisenatide 5 and 10 pg were safe and well tolerated in pediatric and adult patients.

Supportive PD and PK data Adult patients - Descriptive statistics on plasma glucose premeal corrected AUCO:30-4:30h (mmol*hlL) per treatment group - Evaluable PD tion Descriptive statistics on ted GLU-AUCMMW1 [mmol*h/L] Treatment N Mean Median (min ; max) group o 12 17.51 (4.98) 16.50 (9.7 ; 25.7) Lixisenatide 12 10.60 (6.83) 12.08 (5.1 ; 18.6) Lixisenatide 12 1.89 (8.36) 1.01 (-15.9 ; 16.3) pg Pediatric ts - Descriptive statistics Plasma glucose premeal corrected AUC0130-4230h (mmol*h/L) per treatment group - Evaluable PD population Descriptive statistics on Corrected GLU-AUCOSMSO), [mmol*h/L] Treatment N Mean Median (min ; max) group Placebo 9 10.10 (9.57) 7.89 (-2.1 ;21.7) Lixisenatide 9 6.24 (8.53) 3.77 (—3.2 ; 19.9) Lixisenatide 9 8.76 (8.12) 4.63 (-0.3 ; 24.1) 10119 Adult patients — descriptive statistics on AUC0230-4z30h for plasma glucose, on, insulin, and C-peptide per treatment group - Evaluable PD population Descriptive statistics on AUCO;30.4:30h Parameter Treatment N Mean (SD) Median min—max group Plasma Placebo 12 57.18 (12.06) 56.83 (37.4 ; 77.7) glucose (mmol*h/L) Lixisenatide 5 pg 12 47.60 (11.02) 49.08 (29.9 ; 71.2) natlde 10 pg 12 38.37 (11.37) 35.10 (22.5 ; 58.5) Glucagon Placebo 12 647.39 (132.49) 616.77 500.3; 908.0) (ng.h/l.) Lixisenatide 5 pg 12 628.56 (191.49) 591.56 (442.2; 1163.8) Lixisenatide 10 pg 12 564.83 (148.93) 513.67 ; 950.6) insulin Placebo 12 1488.52 1342.19 (763.6 ; 2859.4) h/L) (512.03) Lixisenatide 5 pg 11 1314.15 1268.09 ; 1841.0) (306.08) Lixisenatide 10 pg 12 1015.12 1051.94 (641.6; 1317.8) (261.87) C-peptide Placebo 12 8.73 (1.91) 8.82 (6.0 '; 13.3) (nmol.h/L) Lixisenatide 5 pg 11 8.08 (1.24) 8.65 (5.9 ; 9.7) Lixisenatide 10 pg 12 7.08 (1.24) 7.25 (4.7 ; 9.1) 1 SE (standard error) Pediatric patients - descriptive statistics on AUCO:30-4:30h for plasma glucose, glucagon, insulin, and C-peptide per treatment group — Evaluable PD population Descriptive statistics on AUCOSOMOh Parameter Treatment N Mean (SD) Median min—max group Plasma glucose Placebo 9 45.57 (19.78) 42.81 (19.4 ; 75.9) (mmo|*h/L) natide 5 pg 9 39.60 ) 41.03 (20.7 ; 55.9) Lixisenatide 10 pg 9 44.60 (17.44) 48.87 (17.9 ; 64.4) Glucagon Placebo 9 685.37 (130.00) 695.60 (456.9 ; 918.5) (ng.h/L) natide 5 pg 8 616.84 4) 592.97 (428.4 ; 763.9) Lixisenatide 10 pg 9 644.06 (117.88) 622.34 (444.1 ; 824.9) n Placebo 7 2152.06 (942.87) 2587.48 (801.6 ; 3335.7) (pmol.h/L) Lixisenatide 5 pg 8 2208.53 (1566.96) 1724.15 (405.7 ; 5330.2) Lixisenatide 10 pg 8 2143.02 (1393.59) 1691.69 (506.2 ; 4693.3) C-peptide Placebo 8 9.70 (1.75) 10.14 (6.6 ; 11.6) (nmol.h/L) Lixisenatide 5 pg 8 9.68 (2.74) 9.18 (5.3 ;14.5) natide 10 pg 8 9.55 (3.00) 9.42 (5.3; 14.3) 1 SE (standard error) PK parameter for lixisenatide in plasma (full PK tion) Mean *1 SD AdUltS Pediatric tric Mean) [CV%] LiXisenaiide 5 pg Lixisenatide 10 [.19 Lixisenatide 5 pg leisenaiide 10 [1g N 10% 12 10 9,** Seminar”.

Cmax 26.0 i 15.4 52.8 i 21.7 25.3 i 15.6 33.3 i 24.0 (pg/mL) (22.8) [59.4] (48.8) [41.1] (20.4) [61.7] (27.0) [72.1] tmaxa 1.50 2.50 1.50 0.50 (h) (0.42 - 3.50) (0.42 - 4.50) (0.48 — 4.50) (0.48 - 3.55) AUCiast 101 i 58.0 228 i 89.0 83.0 i 76.8 105 i 102 (pg-h/mL) (90.8) [57.3] (213) [39.0] (57.1) [92.5] (68.9) [97.4] AUCo.54.5 77.2 i 42.4 169 i 72.4 74.7 i 55.2 86.8 i 71.2 (pg-h/mL) (70.0) [54.9] (155) [43.0] (57.9) [73.9] b (65.6) [82.1] Median (Min - Max) * 011; “ 484001001, ”710002007 all samples were below LLOQ. 9 840003002.ll 826001020 ; 1[484001003 no more than 3 consecutive samples were above LLOQ and therefore not evaluable for PK analysis “ N=8, could not be calculated for patients 710002005, 007 , therefore not included in the summary statistics Source = PKS Study: PKD11475;: P-D-A—EV-OD Version 1, P-D—A-EV—OD-EOZ, Version 3 :xampie 5 120 A randomized, double—blind, placebo-controlled, dose escalation, study on safety, pharmacokinetics and pharmacodynamics of lixisenatide in pediatric patients With type 2 diabetes not adequately lled with min and/or basal insulin Clinical Trial Summary Randomized, double-blind, placebo—controlled, dose escalation study on safety, pharmacokinetics and pharmacodynamics of lixisenatide in pediatric patients with type 2 diabetes not adequately controlled with metformin and/or basal insulin TORITRIAL LOCATION Multinational, multicenter STUDY OBJECTIV Primary objective: 0 To demonstrate safety of 14-day repeated lixisenatide doses of 5 pg, 10 pg and 20 pg as compared to placebo pediatric in patients with type 2 diabetes Secondary objectives: . To evaluate plasma concentrations of lixisenatide after repeated doses of 5 pg, 10 pg and 20 pg and pharmacokinetic parameters of repeated lixisenatide doses of 20 pg in plasma in pediatric patients with type 2 diabetes To evaluate the change to ne in post—prandial plasma glucose concentrations during a rdized meal test after repeated doses of lixisenatide 5 pg, 10 pg and 20 pg in comparison to placebo DESIGN Phase l, center, randomized (3:1), -blind, placebo- controlled, dose escalation study The study compn’ses: . An up to 3-week screening period a A 6-week randomized double-blind treatment period with 2 el arms (placebo arm / lixisenatide arm) and incremental sequential steps of 2 weeks for the lixisenatide dose escalation (5 pg, 10 pg and 20 pg) or matched placebo A post-treatment follow-up period of 3 days STUDY POPULATEON Male and female patients with documented type 2 diabetes Main selection ia: mellitus insufficiently controlled with a min dose 2 1000 mg/day (or maximum tolerated dose according to the investigators judgment) at a stable regimen for 8 weeks prior to randomization and/or stable basal insulin alone or in combination for 12 weeks prior to randomization Aged 2 10 and < 18 years old (at least 4 patients below 16 years old) HbAlc >6.5% and s 11 % Body mass index (BMI) of >85th percentile for age and gender and BMI s 50 kg/m2 ; Fasting C-peptide at screening > 0.6 ng/mL Negative test for anti-insulinoma associated protein (IA2) and anti-glutamic acid oxylase (GAD) autoantibodies; Total expected number of patients: A total of 24 completed patients Expected number of sites de STUDY TREATM -NT(s) During the first part of the double-blind treatment period with lixisenatide 5 pg or matching placebo during 14 days: lnvestigational Medicinal Product(s) Test drug: Lixisenatide 5 pg Formulation: Lixisenatide will be supplied as a disposable pro-filled pen, is a self-injector device (Tactipen®) containing 3 mL of a sterile aqueous solution for subcutaneous (so) injection in Route(s) of administration: a 3—mL volume containing 300 pg of the active ingredient (i.e., iOO pg/mL), glycerol, sodium e trihydrate, Dose regimen: methionine, metacresol, HCLjNaOH, water for injection.

Control drug: Lixisenatide matching placebo natide matching placebo will be supplied as a sterile 3-mL aqueous solution. ‘ Both lixisenatide and the matching placebo are to be injected once daily with a pen self-injector device and the volume to be injected will be 50 pL.

Route(s) of administration: s.c.

During the second part of the double-blind treatment period with lixisenatide 10 pg or matching placebo during 14 days: Test drug: Lixisenatide 10 pg natide is supplied as green disposable led pen, ie a self—injector device (Delta 14®) containing 3 mL of a sterile aqueous solution for s.c. injection with 150 pg of the active ingredient (ie, 50 pg/mL), glycerol, sodium acetate trihydrate, methionine, metacresol, CL/NaOH, water for injection. The lixisenatide jector dispenses fourteen fixed doses of 200 pL. l drug: Lixisenatide matching o Lixisenatide matching placebo will be supplied as a sterile 3—mL s solution Both lixisenatide and the matching placebo are to be injected once daily with a pen self-injector device (Delta i4® of green color) and the volume to be injected will be 200 pL. s) of administration: 5.0.

During the third part of the double-blind treatment period with lixisenatide 20 pg during 14 days or matching placebo: Test drug: Lixisenatide 20 pg Lixisenatide is ed as purple disposable self-injector device (Delta 14®) containing 3 mL of a sterile aqueous on for so. injection with 300 pg of the active ingredient (ie, 100 pg/mL), glycerol, sodium acetate trihydrate, methionine, metacresol, HCL/NaOH, water for injection. The natide pen-injector dispenses fourteen fixed doses of 200 pL.

Control drug: Lixisenatide matching placebo Lixisenatide ng o will be supplied as a sterile 3-mL aqueous solution Both lixisenatide and the matching placebo are to be injected once daily with a pen self—injector device (Delta 14® of purple color) and the volume to be injected will be 200 pL.

Routejs) of administration: 3.0.

Before starting each dose escalation step the patients and/or their parents will be trained on site by the study staff/nurse to use each type of injector pens appropriately before they start the new dose of daily subcutaneous injection of lixisenatide or placebo.

Furthermore, if , depending on patients maturity, a home nursing e can be proposed during the first 3 injections (or more if needed) to ensure a good compliance.

At home, injections should be performed once daily within 1 hour prior to breakfast. At on—site visits, ions should be performed once daily approximately 30 s prior to the start of the standardized breakfast.

Background antidiabetic therapy will be stered daily about the same clock time as usually done; ment of basal n dose may be needed with the supervision of the investigator or medical designee.

Non lnvestigational Medicinal Product(s) Not applicable (if applicable) Formulation: s) of administration: Dose regimen PRIMARY ENDPOINT(S) AN Primary endpoint: ARY NT(S) gajgty: Adverse events (AEs) Nreatment—Emergent Adverse Events (TEAEs) clinical laboratory (hematology, biochemistry, lipase and amylase, urinalysis) evaluations including vital signs, 12—lead ECG parameters, body temperature and physical examination.

Secondary nts Pharmacokinetics: . PK parameters (Cmax, trnax, ,AUCth.5)after14—day repeated dosingat20 pg on Day 42 Lixisenatide plasma concentrations 0, 0.5, 1.5 and 2.5 hours after lMP injection, i.e. T0 before IMP, T05, T15 and T25, after 14-day repeated dosing at 5 pg, 10 pg and 20 pg on Day 14, Day 28 and Day 42; Pharmacodynamics: . The change to baseline in plasma glucose AUC04.5 after 14-day repeated dosing at 20 pg on Day 42 The change to baseline in postprandial plasma glucose excursion 1H post meal test and 2H post meal test, i.e. difference T1,5—T0 and T2.5—TO after 14—day repeated dosing at 5 pg, 10 pg and 20 pg on Day 14, 28 and 42, Anti—lixisenatide antibodies: assessment before first dosing at Visit2Da -1 ,and after14-day re-eated dosin- at5 -, 10 q and 20 pg.

Other endpoints Body weight, HbA1c at baseline and after 14-day repeated dosing at 20 pg.

ASSESSM NT SCH Screening period: from Week—3 to Week -1 At Visit 2 (Day-1): face to face ng of patients and/or (s) on IMP pen injector, glucose meter use, diary recording use, hypoglycemia awareness and management education; IMP subcutaneous injection training for the home nurse e, if any, in charge of the administration of the appropriate dose and in the respect of given condition (outpatient procedure excepted at on—site visits). ne pharmacodynamics assessments with blood sampling 0.5 hours prior to the standard breakfast ingestion (ie, T0). Then blood sampling will be performed at 1, 1.5, 2, 2.5, 3.5 and 4.5 hours after breakfast (ie, T1, T15, T2, T25, T35 and T45).

Randomized, double-blind placebo-controlled treatment period with dose escalation every 14 days (5 pg, 10 pg and pg or matching placebo) Every 2 weeks, on—site visits: Visit 3 (Day14), Visit 4 (Day28) and Visit 5.(Day42) for , pharmacodynamics and pharmacokinetic assessments These on—site visits require patients to be in fasting condition for blood sampling prior to IMP injection (approximately 30 min before the start of the standard breakfast, is TO). Then, blood sampling will be performed at the following ints: o 0 (immediately before IMP ion), 0.5 (PK only)15 and 2.5 hours after IMP injection (ie TO, T05, T15 and T25) at Visit 3 (Day14) and Visit 4 ) . 0, 0.5 (PK only), 1, 1.5, 2, 2.5, 3.5 and 4.5 min (ie TO, T05, T1, T1 .5, T2, T25, T35 and T45) at Visit 5 (Day 42) Safety: refer to the study flow chart for physical examination, body temperature and vital signs, 12-lead ECG, and laboratory assessments. Throughout the study :adverse events recording STATISTICAL CONSIDERATIONS All analyses will be interpreted in an exploratory way, no confirmatory analyses will be done.

Safety: All randomized patients receiving at least one dose of the IMP (regardless of the amount of treatment administered) will be included in the safety tion.

The safety analysis will be conducted on the safety population based on individual values (clinically cant abnormalities) and descriptive statistics (summary tables and plots if riate). Individual values will be flagged for potentially . clinically cant abnormalities (PCSAs), TEAEs will be tabulated s and percents). Descriptive statistics will be generated by dose level/treatment for selected parameters of interest.

Vital signs, Laboratory— and ECG parameters and changes com-ared to baseine where a roriate will be anal zed b dose level/treatment using descriptive statistics.

Number and percentage of patients with antibody status negative/positive will be summarized by dose level.

Pharmacokinetics (PK): Plasma AVE0010 concentrations will be summarized by antibody status for each dose level using descriptive statistics. PK parameters (Cmax, tmax, AUCM5) will be summarized by antibody status for the 20 pg dose level using descriptive statistics.

Pharmacodynamics (PD): Descriptive statistics and graphs will be provided on raw data and change from ne. Analyses will be done by dose level/treatment.

Relationship between PK and PD will be explored graphically at the 20 pg dose level.

Results from PK modeling and PK/PD analysis will be reported separately.

Others es: ptive statistics and graphs will be provided on raw data and absolute change from baseline for HbAtc, and body weight.

DURATION OF STUDY PERIOD Duration of each part of the study for one patient: (per patient) Screening: Day-21 to Day-1 (overnight hospital stay from Day-1 to Day 1 or two single visits ) Treatment period: 6 weeks (Day 1 to Day 42) with on- site visit prior to the dose escalation every 2 weeks -up and end-of-study: Day 45 Total study duration: up to 10 weeks 1. FLOW CHARTS 1.1. GRAPHICAL STUDY DESIGN The graphical study design of Example 3 is shown in Figure 17.

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After a meal, lixisenatide activates the following individual physiologic ses: 0 Enhances insulin secretion by B—cells in a glucose ent way 0 Suppresses glucagon secretion by s o Delays gastric emptying Lixisenatide stimulates insulin secretion only when blood glucose is increased, but not at euglycemia, which limits the risk of hypoglycemia. In parallel, glucagon secretion is ssed.

In case of hypoglycemia0 the rescue mechanism of glucagon secretion is preserved. Lixisenatide also slows gastric emptying thereby reducing the rate at which meal—derived glucose s in the circulation. The effect on gastric emptying may contribute to body weight ion.

Lixisenatide further showed a trend towards insulinotropic activity, including enhancement of insulin biosynthesis and stimulation of beta-cell proliferation in animals, and has been shown to preserve beta cell function and prevent cell death (apoptosis) in ed human pancreatic islet cells.

In summary, lixisenatide is an exendin analog with strong GLP=~1 agonistic activity. The pal therapeutic potential of lixisenatide to lower blood glucose in adult T2DM patients has been established in clinical studies.

Lixisenatide (Lyxumia®) was ed since 2013 in the European Union, Japan, Mexico and other parts of the world for the treatment of adults with T2DM to achieve glycemic control in combination with oral glucose lowering medicinal products and/or basal n when these, together with diet and exercise, do not provide adequate glycemic control. The indication may vary slightly across the countries where natide is approved.

According to the Summary of Product Characteristics, the 10 ug dose is the starting dose intended to improve gastrointestinal tolerability. After 2 weeks at 10 ug QD, the dose should be increased to 20 ug QD from Day 15. The 20 ug dose Q ») is the fixed maintenance dose.

Up to now, the safety and efficacy of the GLP-1 or agonists currently approved in the U.S. have not been established for use in patients less than 18 years of age. Therefore, there is little clinical evidence upon which to base a discussion of anticipated therapeutic similarities or differences between pediatric and adult patients with T2 M administering these agents.

In a single—dose pharmacokinetic study conducted with exenatide in 13 patients with type 2 diabetes and between the age of 12 and 16 years, administration of exenatide (5 pg, the initiation dose in adult) resulted in slightly lower mean AUC (16% lower) and Cmax (25% lower) compared to those observed in adults (12). Based on the ural similarities of lixisenatide and ide, these results may be taken into consideration when ing the clinical studies proposed with lixisenatide.

A previous PK/PD study (Example 2) in type 2 diabetic children and adolescents (from 10 to 17 years) and in type 2 diabetic adults (as a control group) was a multicenter study evaluating PK, safety/tolerability and PD ters after single 8.0. administration of lixisenatide 5 pg, 10 pg and placebo ing to a ized, double-blind crossover design. All included patients were previously d with metformin. In 12 pediatric patients, a non-significant decrease in plasma glucose (plasma glucose AUC0;30h4;30h) after a standardized liquid breakfast was observed with single doses of lixisenatide 5 and 10 pg compared to placebo. In contrast, these single doses of lixisenatide significantly reduced plasma glucose ed to placebo in 12 adult patients with T2 M. Lixisenatide exposure was similar for both dose groups in the evaluable pediatric patients, whereas in adult patients, the lixisenatide exposure dose-proportionally increased. In pediatric patients, the exposure was similar to that in adults for lixisenatide 5 pg, but lower for lixisenatide pg. Single doses of lixisenatide 5 and 10 pg were safe and well tolerated in both, pediatric and adult ts in this study of short duration.

In conclusion, Example 2 demonstrated comparable PK and PD profiles in pediatric and adult patients at a dose of Spg, as well as no unexpected safety results. However, the results observed with a dose of IOpg (initiation dose in adult) are not conclusive. The dose of 20pg (maintenance dose in adult) was not evaluated in this study.

As a consequence, this repeated dose study will therefore be conducted to further evaluate PK, PD and safety at a dose of 5, 10 and 20pg before conducting a large phase 3 study with the expected therapeutic dose.

More detailed information on lixisenatide (AVEOOlO) is ed in the Investigator’s Brochure. 2.2 AL III 2.2.1 Study Rationale The aim of the present study is to evaluate safety, cokinetics and pharmacodynamics of repeated subcutaneous QD dose administration of lixisenatide.(5 pg, 10 pg and 20 pg) versus placebo in pediatric patients with type 2 diabetes (10—17 years old).

T2DM in children and adolescents has become an singly important public health concern throughout the world. T2DM occurs when insulin secretion is inadequate to meet the increased demand posed by insulin resistance, leading to relative insulin deficiency (l) and is frequently associated with other lic abnormalities, characteristic of insulin resistance (dyslipidemia, hypertension, polycystic ovary syndrome, fatty liver) (2). ding with the increasing prevalence of obesity in children, the incidence of T2DM in children and adolescents has ly increased. Obesity is a major risk factor impacting insulin sensitivity and leading to T2DM in pediatric patients.

The pathophysiology of T2DM in children and adolescents appears to be similar to that in .

The increase in diabetes in a younger population is likely to be related to the increase in obesity in this population.

One study found an inverse relationship between body mass index and age at diagnosis of T2DM t adults, and it is possible that the degree of y determines when es will develop. It is then reasonable to assume that such glucose-lowering agents associated with weight reduction will be effective in the pediatric population. r, some factors, such as the number of associated co—morbidities in the different age groups, and differences in the management of en / adolescents as compared to adults, make it difficult to estimate the similarities and differences of treatment effects in T2 )M between these two populations.

At present, metformin and insulin are the only drugs with regulatory approval in most countries for the ent of pediatric diabetes. necause approximately half of youth with T2DM fail to maintain glycemic control when treated with metformin either alone or in conjunction with lifestyle interventions, insulin therapy is often required soon after diagnosis. Thus, there is a need for more treatment options for children and cents with T2DM. 2.2.2 Design Rationale and risk assessment This is a centric, ized, -blind, placebo—controlled, repeated dose study with lixisenatide dose escalation by 2-week step ng at 5 ug, followed by 10ug and 20ug. 0 Study population The study population will include male and female patients aged between 10 and 17 years old inclusive.

Use of GLP—l receptor agonists may be associated with gastrointestinal adverse reactions.

Therefore, pediatric patients with severe gastrointestinal disease associated with prolonged nausea and vomiting, including severe gastroparesis will not be included in this study. To date, there is limited therapeutic experience of lixisenatide in adult patients with moderate renal impairment and no therapeutic experience in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease. As a consequence, pediatric patients with severe renal impairment will not be ed in the present study. 4» Doses and regimen In the present study, lixisenatide treatment will be initiated with 5 ug Q3 during 2 weeks then increased to 10 ug QD for 2 weeks then 20 ug Q.) for 2 weeks. This stepwise dose increase can prevent or reduce gastro—intestinal adverse events frequently observed with lixisenatide. The dose of 5 pg corresponds to 50 % of the starting dose in adults, and 20 ug Q) is the maintenance dose in adults. This study will assess liXisenatide given in combination with metformin and/or basal insulin.

Patients will be included with a stable dose of metformin (unchanged for at least 8 weeks prior to randomization) and the initial metformin dose is to be kept unchanged throughout the study. The metformin morning dose will not be taken before the last blood sample and it may be delayed at lunch time or later.

When liXisenatide is added to existing y of basal insulin, a reduction in the dose of the basal insulin may be considered to reduce the risk of hypoglycemia, possibly when starting the dosing with 20 ug, at the discretion of the igator. 0 Condition of administration Lixisenatide should be administered by deep subcutaneous injection, alternating between the left and right anterolateral and left and right posterolateral abdominal wall, thighs or upper arms.

Within a given area, on should be changed (rotated) at each time to prevent injection site skin reactions.

Lixisenatide will be subcutaneously administered on site approximately 30 minutes before the start of the standardized breakfast on Days 14, 28 and 42.The other days, it will be administered within 1 hour before breakfast in outpatients. 2.2.3 Specific ters rationale Hypoglycemia and symptomatic hypoglycemia will be carefully monitored by reporting of adverse events and r control of glycemia; appropriate device for self-monitoring plasma glucose (monitored by parents) will be provided to participants (Section 4.2.2).

The monitoring of pancreatic enzyme levels will be applied in this study. This is an eStablished practice in clinical trials involving glucagon-like peptide—l or agonists following reports of pancreatitis during T2DM treatment with this therapeutic class (3). Diagnosis of pancreatitis required meeting of two of the following three criteria: amylase/lipase levels three or more times the upper normal limit, characteristic nal pain, and/or characteristic findings of acute pancreatitis on computed tomography scan or ic nce imaging.

Anti—liXisenatide antibody formation may occur. Therefore, they will be measured before first closing at Day— 1(baseline), and after 14-day repeated dosing at 5 pg, 10 pig and 20 ug. Systemic allergic reactions may occur, as well as other hypersensitivity ons that have been observed in natide clinical trials, eg, rash or ema, ria, angioedema and anaphylactic reactions. Hypersensitivity reactions may occur, with or without the presence of anti-liXisenatide antibodies. 2.2.4 Study committees The sponsor can ask the opinion from independent experts in the field of allergy to review the cases of allergic or allergic—like reactions in a blinded manner with regard to study ent.

Similarly, in cases of pancreatitis, the events can be reviewed by independent gastroenterology experts. 3 SELECTION OF PATIENTS 3.1 lNCLUSlON CRITERIA Demography I 01. Vlale or female ts aged 2 10 and < 18 years old (at least 4 patients below 16 years I 02. %ody mass index (BMI) >r85th percentile for age and gender ; %MI < 50 kg/m2 ; body weight > 50 kg Health status I 03. Male and female patients with nted type 2 diabetes mellitus insufficiently controlled with a metformin dose 21000 mg/day (or maximum tolerated dose according to the Investigator’s judgment) at a stable n for 8 weeks prior to randomization and/or stable basal insulin alone or in combination for 12 weeks prior to randomization 104. HbAlc > 6.5% and 511% at screening I 05. Fasting C-peptide at screening > 0.6 ng/mL (0.20 nmol/L) l 06. Negative test for anti-insulinoma associated protein (1A2) and anti-glutamic acid oxylase (GA )) autoantibodies I 07. Menstruating females(even if irregular) must have a negative pregnancy test for ion and agree to repeat pregnancy tests at designated visits throughout the study.

Regulations 1 08. Provision of Informed Consent form signed by the patient’s parent (s)/1ega1 representative. in addition, provision of Assent Form signed by minor t or Informed Consent Form signed by emancipated or mature minors (defined by local laws) I 09. Covered by a health insurance system where applicable, and/or in ance with the recommendations of the national laws in force relating to biomedical research. 1 10. Not under any administrative or legal supervision. 3.2 EXCLUSION IA 3.2.1 ion criteria related to study methodology E 01. If female, ongoing ncy (defined as positive serum pregnancy test), breast—feeding E 02. Sexually active narchal female patient who does not agree to use an adequate and highly effective method of contraception throughout the study duration and according to local regulation (i.e. hormonal contraception, condom, etc.). *1 03. Diabetes other than type 2 diabetes E 04. History of acute lic decompensation such as ic ketoacidosis within 3 months Lil 05‘. g plasma glucose > 250 mg/dL (>139 mmol/L) at screening E 06. Hemoglobinopathy or hemolytic anemia ill 07. Recurrence of severe hypoglycemia or hypoglycemic unawareness as judged by the investigator ‘3‘ 08. Uncontrolled hypertension, treated or untreated above 99th percentile for age and gender in children (see Appendix A) E 09. Any clinically significant abnormality identified on physical ation, laboratory tests, ECG or Vital signs at the time of screening that in the judgment of the Investigator or any sub Investigator would make implementation of the protocol or interpretation of the study results difficult or would preclude the safe participation of the patient in this protocol such as active malignant tumor diagnosed hyperthyroidism or uncontrolled hypothyroidism or major systemic diseases etc. (euthyroid patients on replacement therapy will be included if the dosage of in is stable for at least three months prior to screening Visit) E 10. Receipt of blood or plasma products within 3 months prior to the time of screening E11. Patient/Parent(s) considered by the investigator or any sub investigator as opriate for this study for any reason (eg, impossibility to meet specific protocol requirements, such as led visits, administer s.c. IMP QD self-inj ection or refusal of any ance of home nurse service for the s.c. IMP injections, etc) 4 l2. Use of other oral or inj e antidiabetic or hypoglycemic agents other than metforrnin and basal insulin (eg, alpha glucosidase inhibitor, GLP-1 receptor agonist, DPP~IV inhibitors, short-acting insulin etc.) within 1 months prior to the time of screening €13. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one week or more within 3 months prior to the time of screening E 14,. Patient having received or receiving psychotropic medication E 15. Patient receiving treatment with weight reduction medications (including anti-obesity treatment) E 16. Likelihood of ing treatment during the screening phase and treatment phase with drugs not permitted by the al study ol * 17. Use of any investigational drug within 3 months prior to screening 3.2.2 Exclusion criteria related to the current knowledge of lixisenatide E 18. Clinically relevant history of gastrointestinal disease associated with prolonged nausea and ng, including, but not d to gastroparesis and gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening E 19. Any previous treatment with lixisenatide E 20. Allergic reaction to any GLP—lreceptor agonist in the or to metacresol E 21. History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease E 22. al or family history of medullary thyroid cancer (MTC) or genetic ions that predispose to MTC (eg, multiple endocrine neoplasia syndromes) E 23. Known y of drug or alcohol abuse Within 6 months prior to the time of screening 4; 24. Laboratory findings at the time of screening: — Elevations in blood tests of renal (serum creatinine >1.0 mg/dL) and/or liver (ALT, AST and/or bilirubin) >2 times the upper limit of normal (ULN) for age.

- Hemoglobin <11 g/dL and/or neutrophils <1500/mm3 and/or ets <100 000/mm3 - Calcitonin 220 pg/mL — Amylase and/or lipase above 3 times the upper limit - Positive result on any of the following tests: hepatitis B e (HBs Ag) antigen, anti~hepatitis C virus (anti-HCV) antibodies E 25. Positive alcohol breath test B 26. Positive result on urine drug screen (amphetamines/methamphetamines, barbiturates, benzodiazapines, cannabinoids, cocaine, opiates) E 27. Severe renal impairment defined With creatinine clearance < 30 mL/mjn/ 1 .73m2 using the revised Schwartz a (4) 0.413 * Ht GFR = Cfserum CrCl (mL/min/1.73 m2) — Ht: Height in cm — Crsemm (mg/dL) 4 ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 4.1 CODYNAMICS 4.1.1 Pharmacodynamic parameters a Plasma e — the change to baseline in plasma glucose AUC0-4,5 age, 14-day repeated dosing at 20 ug on Day 42 (GLU—AUCM‘sy GLU— AUCO 45 is defined as the area under the plasma glucose concentration time profile from time of the IMP injection until 4:30 hours later (T45). AUC will be calculated using the trapezoidal rule. — the change to baseline in postprandial plasma glucose excursion 1 hour andial and 2 hours postprandial after l4-day repeated dosing at 5 pg, 10 ug and 20 ug on Day 14, 28 and 42: o postprandial plasma glucose excursion 1 hour post prandial (lH-PPG) will be calculated as the difference between the plasma glucose value 1 hour post meal test (T15) and the plasma glucose value before time of injection (T0): lH-PPG = PG-T1.5 — PG—TO o postprandial plasma glucose ion 2 hours post prandial (2H—PPG) will be calculated as the difference between the plasma glucose value 2 hours post meal test (T25) and the plasma glucose value before time of injection (T0): 2H—PPG = PG—T2.5 —- PG—TO o HbAlc - Change from baseline to Week 6 0 Body weight -— Change from baseline to Week 6 4.1.2 Assessment methods 4. 1.2. 1 Plasma glucose Plasma e ments are planned on )ay -1 (V2) (Baseline), Day 14 (V3), Day 28 (V4) and Day 42 (V5). Blood samples will be taken as indicated below in Table l Table 1 — Blood sampling for plasma glucose Time 0 H 1H 1H30 2H 2H30 3H30 4H30 (hour/min) T (h) To a T1 T1.5 T2 T2.5 T35 T45 Visit/Day: V2/Day-1 X X X X X X X V3/D14 X X X V4/D28 X X X V5/D42 X X X X X X X a 30 min before to the standardized breakfast ingestion and prior to IMP administration at V3/D14, V4/D28 and V5/D42 The first blood sampling (T0) for plasma glucose will be withdrawn in fasting condition (i.e., patients will be fasted for imately 10 hours overnight), 30 min prior to the standardized breakfast and prior to dosing on Days 14, 28 and 42.

Samples for plasma glucose will be analyzed in a Central laboratory. Detailed ation on sample drawing, management and bioanalytical methods for plasma glucose will be provided in the laboratory manual. 4.1.2.2 HbA1c HbAlc will be ed by a central laboratory certified level I “National Glycohemoglobin Standardization Program” (NGSP) central laboratory.

TIbAlc will be measured at screening (V1) and Day42 (V5).

Detailed information on sample g, management and bioanalytical methods for HbAlc will be provided in the tory manual. 4. 1.2.3 Body weight 3ody weight should be obtained with the patient wearing undergarments or very light clothing and no shoes, and with an empty bladder. The same scale should be used throughout the study, and calibrated on a regular basis as recommended by the manufacturer.

The use of balance scales is recommended; if digital scales are used, testing with rd weights is of particular importance. The floor surface on which the scale rests must be hard and should not be carpeted or covered with other soft material. The scale should be balanced with both s at zero and the balance bar aligned. The patient should stand in the center of the rm as standing nter may affect measurement. The weights are moved until the beam balances (the arrows are aligned). The weight is read and recorded in the e-CRF and Source Data. Self—reported weights are not acceptable; patients must not read the scales themselves.

Body weight will be ed at screening, on )ay -1, Dayl4, Day 28, Day 42 and at the end of the. study Visit. 4. 1.2.4 Patient diary ation recorded into diary will document the compliance of IMP (liXisenatide/placebo) treatment as well as the safety and tolerability and these recordings will be carefully reviewed also at each on—site visit.

All patients will receive 1 diary, at visit V2 and they will bring it back to the center at each following visit during the treatment. Patients/parents will be instructed how to fill in it every day.

The diary includes sections for recording: Time and dose of IMP injections (during the treatment ), Any change in metforrnin dose or missing ) and time if any, Any change in basal insulin daily dose and time or missing_dose(s)if any, ‘Any change or new concomitant medication, Adverse events, including signs and symptoms suggesting occurrence of hypoglycemia (possibly documented with measurement of “self—monitored plasma glucose” or plasma glucose monitored by others) and local injection site reactions, if any.

All patients will receive 1 diary, at visit V2 and they will bring it back to the center at each following visit during the treatment. Patients/parents will be cted how to fill in it every day. 4.1.3 Assessment schedule The assessment timing can be found in the period flow chart (Section 1.3).

Table 2 — Number of samples Plasma glucose HbA‘l c By t (7X2)+(3x2) a 2 Total by patient 20 2 Total for study (n patients) 20 * 24:480 2 * 24:48 a 7 timepolnts at Day‘t (V2) and Day 42 (V5) — 3 timepoints at days 14 and 28 (V3 and V4) , 4.2 SAFETY Assessment schedule should be adapted to the compound specificities and the objectives of the study. Suggested list below: 4.2.1 Baseline demographic teristics: ne demographic characteristics will consist of: 1. Age (years) P‘EJ‘PP’N Height (cm) Body weight / Body mass index Race / Ethnicity Gender Diabetes history including: — Date of the diagnosis of diabetes; — Start date, daily dose and regimen of administration of the background treatment at screening: metformin, basal insulin if any 7. Tanner staging (Appendix B) 4.2.2 Safety assessment at baseline and during the study The tolerability investigations at baseline and during the study will consist of: 1. Physical examination (includes at a minimum: heart and respiratory auscultation; eral arterial pulse; pupil, knee, es, and plantar reflexes; peripheral lymph nodes and abdomen examination), Body temperature (°C), Vital signs (heart rate, systolic and lic blood pressure measured after 10 minutes in supine resting position). ody weight (kg).

. Laboratory tests (in fasting ions for blood samples): 0 Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), platelets. 0 Biochemistry: - Plasma/serum electrolytes: sodium, potassium, chloride, calcium; = Liver function: AST, ALT, alkaline phosphatase, gamma-glutamyl erase, total and conjugated bilirubin; - Pancreatic enzymes: amylase, lipase — Renal function: urea, nine; - Metabolism: glucose, albumin, total proteins, total terol, triglycerides; _- Potential muscle toxicity: creatine phosphokinase, ‘- Calcitonin (thyroid c-cell tumor marker) at screening only 4. gy tests: hepatitis B antigen, hepatitis C antibodies . Urinalysis: proteins, glucose, erythrocytes, leucocytes, ketone , and pH. (To be adapted according to investigator site dipsticks) — Qualitative: A dipstick is to be performed on a freshly voided en for qualitative detection using a reagent strip.

— Quantitative: A quantitative measurement for glucose, protein, erythrocytes, and ytes count will be required in the event that the urine sample test is positive for any of the above parameters by urine dipstick (eg, to confirm any positive dipstick parameter by a quantitative measurement).

Urine drug screen: amphetamines/metharnphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates.

Alcohol breath test.

If , beta~HCG plasma test.

Anti-lixisenatide antibodies . Adverse events, spontaneously reported by the patient or observed by the Investigator, will be monitored; ll. Standard lZ-lead ECGS (safety ECGs) are ed after at least 10 s in supine position using an (type of recorder and company to be added) electrocardiographic device.

The electrodes will be positioned at the same place for each ECG recording throughout the study (attachment sites of the leads will be marked with an indelible pen). 11 case of triplicate (ie, baseline in TDU), 3 ECGS will be recorded within 5 minutes with at least 1 minute between 2 replicates. *ach ECG consists of a lO—second recording of the 12 leads simultaneously, leading to: o A single 12-lead ECG (25 mm/s, lOrnrn/mV) printout with heart rate, PR, QRS, QT, QTc automatic correction evaluation (by the ECG device), ing date, time, initials, and number of the patient, signature of the ch physician, and at least 3 xes for each lead. The Investigator’s medical opinion and tic values will be recorded in the e-CRF. This printout will be retained at the site. o A digital storage that enables eventual r reading by an *‘CG central laboratory: each digital file Will be identified by theoretical time (day and time DXXTXXHXX), real date and real time (recorder time), Sponsor study code, t number (ie, 3 digits), initials (ie, 3 ters), and site and country numbers, if relevant. The digital recording, data storage, and transmission (whenever requested) need to comply with all applicable regulatory requirements (ie, F )A 21 CFR, part 11). 12. Self—monitored plasma glucose measurement All the patients will be supplied with a plasma glucose meter, the corresponding supplies (lancets, test strips, etc.) and with diaries at visit V2 (Week- 1)1n order to perform self- measurement of plasma glucose (or by others) and its recording. The glucose meters should be calibrated according to instructions given in the package leaflet and the study site should also check the glucose meters regularly using the provided control solutions for data ty. At visit V2 (week ~l) patients and their “referent parent(s)” will be trained to accurately measure plasma e values with the glucose meter. The patients will be instructed to bring their glucose meters with them to each on—site visit.

It is the investigator’s responsibility to explain the need to measure glucose at the times indicated below. Training will be repeated as often as necessary at the study visits and the study site staff reviews the patient’s diary at each visit. Plasma glucose values will be measured by the patient/parent using the sponsor-provided blood e meter and recorded1n the patient diary.

The patient will be instructed to perform SMPG ements: - Fasting value at least 3 times a week or more for ts treated with basal insulin, as medically indicated 0 And for all patients treated with or without basal insulin, whenever a measurement is considered helpful, e.g. whenever the patients feel hypoglycemic ms, plasma glucose should be measured by the patient (or others, if able), if possible. ts should be instructed to e plasma glucose levels prior to the administration of glucose or carbohydrate intake whenever hypoglycemia is suspected (see XX of the protocol) unless safety considerations necessitate immediate e/carbohydrate countermeasure prior to confirmation. The values will be entered in the patient” 3 individual diary and transcribed into the e—CRF. 4.3 ANTI—LIXIS ENATIDE ANTIBODIES 4.3.1 Sampling times Plasma samples from all patients will be collected to determine anti—lixisenatide antibodies on Day —1 / )ay 14 / Day 28 /Day 42 before the study drug administration . Procedures for collection, storage, and shipment will be provided in a te manual. 4.3.2 Number of samples Table 3 ~ Number of plasma samples for anti—lixisenatide antibodies Anti-lixisenatide antibodies Total by patient 4 Total for patients (n=24) 96 4.3.3 Sample handling procedure for anti-lixisenatide antibodies Table 4 - Bioanalytical method Analyte Anti- natide dies Matrix Plasma Analytical Technique BIAcore Lower Limit of Quantification cut—off Assay Range not relevant Assay Volume 100 uL Site of Bioanalysis Dept. of ition, Safety and Animal Research (DSAR), sanofi aventis, Frankfurt Method Reference RPSMPK—DOHO754-BM1~EN~E01 4.4 PHARMACOKINETICS 4.4.1 Sampling times The sampling times for blood collection can be found in Table 5 and in the period flow chart (Section 1.3).

Table 5 - Blood sampling for lixisenatide plasma concentrations Time 0 H 0H30 1 H 1H30 2 H 2H30 3H30 4H (hour/min) T (h) T0 a T0.5 b T1 T1.5 T2 T25 T35 T45 Visit/Day: V3/D14 P00 P01 P02 P03 V4/D28 P00 P01 P02 P03 V5/D42 P00 P01 P02 P03 P04 P05 P06 P07 a Prior to IMP administration b Just prior to the standardized breakfast ingestion 4.4.2 Number of pharmacokinetic samples Table 6 — Number of plasma samples lixisenatide By patient (4 x2)+8 =16 Total for study (n patients) 16 * 24:384 a 4 timepoints at Day14 (V3) and Day 28 (V4) — Btimepoints on Day 42 (V5) 4.4.3 Sample ng procedure Special procedures for collection, storage, and shipment should be provided in the laboratory manual.

Table 7 — Summary of handling procedures Blood sample volume 2 mL Anticoagulant K3 EDTA ng procedures “See Appendix B of the protocol Plasma aliquot split 2 tubes with one containing at least 0.5mL Plasma storage conditions —20°C Plasma shipment ions On dry ice 4.4.4 Bioanalytical methods Lixisenatide plasma concentrations were determined using a validated double antibody sandwich enzyme linked immunosorbent assay method with an LLOQ (lower limit of quantification) .5 pg/mL and an assay volume of 120 uL.

Table 8 — Summary of bioanalytical method Analyte llxisenatide Matrix Plasma Analytical technique Double-antibody ch ELISA Lower limit of fication 5.5 pg/mL Assay volume 120 pL Site of bioanalysis Covance laboratories lnc, Chantilly, France Method reference VA 20151-1130 / DOH1317 4.4.5 Pharmacokinetic parameters The following pharmacokinetic parameters will be calculated, using noncompartmental methods from plasma concentrations obtained after repeated dose administration. The parameters will include, but may not be limited to the following.

Table 9 — :ist of pharmacokinetic parameters and ions ters Drug/Analyte Matrix tion/Calculation Maxrmum plasma concentration observed during the respective treatment lixisenatide Plasma Cmax period, tmax lixisenatide Plasma Time to reach Cmax Area under the plasma concentration versus time curve calculated using the AUCOAEO Iixisenatide Plasma trapezoidal method from time zero (lixisenatide scale) to time 4.30 hours post 4.5 SAMPLED BLOOD VOLUME Sample blood volume should be presented in a table.

Table 10 — Sampled blood volume per patient Type Volume per sample Sample number Total Serology tests 2.5 mL 1 2.5 mL Auto anti—bodies 3.5 mL 1 3.5 mL Calcitonin 2.0 mL 1 2.0 mL B-HCG (if able) 1.1 mL 1 1.1 mL Hematology 2.0 mL 2 4.0 mL Biochemistry 2.5 mL 2 5.0 mL Amylase, lipase only 2.5 mL 4 10.0 mL HbA1c 2.0 mL 2 4.0 mL Plasma glucose 1.2 mL 20 24 mL Pharmacokinetlcs Lixlsenatide 2 mL 16 32 mL Antl-lixlsenatide antibodies 1 mL 4 4 mL Total if male 91 mL Total if female 92.1 mL The approximate total sampled blood volume in children is 91 and 92.1 mL for male and. female patients, tively (approximate due to discarded blood When catheter is set up at each period).

The amount of blood volume per visit will not exceed 32 mL (the highest at Visit 5). onal samples may be needed if any laboratory result is outside of the normal range or for safety purposes. 4.6 FUTURE USE OF SAMDLES Not applicable.

BIBLIOGRAPHIC REFERENCES 1. Druet C, Tubiana—Rufi N, Cheyenne D, Rigal O, Polak M, archal C. terization of insulin secretion and resistance in type 2 diabetes of adolescents. J Clin Endocrinol Metab 2006: 91: 4014, 2. Miller J, Silverstein JH, Rosenbloom AL. Type 2 es in the child and adolescent. In: Lifshitz F (ed) Pediartric Endocrinology: fifth edition, volume 1. New York, Marcel jekker 2007: pp 169—88. 3. Olansky L.: ' ‘echnol )o incretin—based therapies cause acute pancreatitis? J Diabetes 2010; 4:2228—9 4. Schwartz GJ, Mufioz A, Schneider QF, Mak RH, Kaskel F, Warady 3A, et al. New Equations to Estimate GFR in Children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629—37 Appendix A Blood pressure levels by gender, age and height Blood Pressure Levels for Boys by Age and Height Percentile Systolic BF {mafia} Dias‘mfic BF {1mm £- tile of Height -) Age Permenfile {— Pam-11143112 131111219111 '5' 4" 36311 95th 5th 1133311: 2531 50th T583 3% 35131 V 19th 2581 513111 75121 111. 53111; a? 98. 111:) 102 111131 1135 1116 53 5e 61: a1 51 52 11:1 911111 111 112 1.14 115 11? 1'19 119 m 13 '11 75 7'11 17 73 115111 115 1111. ‘ 11:1 1191 121 122 123; 3? 13: re 8:1 a1" a1" 13': . 919111 ’ 12:1. 12:1 125 12? 1211 1311 131:1 ‘85 3e $15 Be as are e11 7 V 11 5011 131; 1.02 1114 1117 51:1 59 a1 132 e3 90211 1 13 114 115 1 11' 1 1e 121:1 121 7'4 14 15 m 77 13 713 95:11 11.7 1 1e 1 111 1:21 123 121 125 13 713 :11: 313 El 32 a: 99111 12.1 125 12? 129 1.2111 1%... 1% as 1311 5? as see so so 1:: 511111 1111 1112 1131 me 11:13 1:19 1111 59 er} e1 e2 53 33 34 219111 115 11a 1111 m 121 12:3 12:1 74 1'5 11-5 75 77 :15 711 95111 1 19 1:21} 122: 1.23 125 127 12? 13 79 ea 31 32 32 113 99111 125 12? 1a 131 133 134: 135 as 111' as 119 911 911 111 13 5111-1 1134 1135 1m 2113 1111 111 112 51:1 5:1 51 32 ea 51 134 me '1 1.7 1 151 1211 122 124 125 125. 1'5 15 715 1? 73 1e 79 95211 121 122 1:24 1215 12a 1:21 1311 1:: 111 e11 111 =32 2:3 '83 age; 123 1,30 131 133 1:35 1311 137' a? 31' e3 39 9e 91 91 14 5pm 1116 1117 11311 1 1'1 '1 13 1 14 115 6111 61 52 ea; 64 as .55 913111 1211 121: 12:1 125 12g 133 123 1'5 111 17 7e 71 m 130 515111 124 125 127 123 1311 132 132 an 1211 e1 32' 33 e1 34 99211 131 1:12 131 135 1311 1:11 1411 a? as ea 91: a1; 92 e2 511:1: we 1 11} 11:1. 1 1:3 1 15 117 11? e1 152 63 B4 115 as ea mm 122 124 125 1.2? 1:21; 1311 131 .75 77 :13 m as eat 31 e511 123 121' 1211 131 133 131 135 111 31. 52 as 211 .35 95 913111 131 1:35 1315 133 1111 1.42 142 as es ea 21 .132 93 e3 59111 1 1 1: 1 12 1 14 113 11s 11s 12-»: :53 83 e1 55 as a? E? 913111 125 123 123 13:13 131 133 1:11 we 13 7:: as 31 82 a: 95111 1213 1:111 132 1321 135 137 13:1 32 33 :33 e1 es ea 51? 99:1: 133 131 139 1111 1'13 111 145 so 131} 91 92 193 94; e4 17 511111 1 14 1 15 115 1 123 1211 121 1a are 115 as er 133 as; R1 911111 1:11 123 1311 13:2 131 135 135 £113 131} 31 a: =33 e1 e4 @5111 131 1:32 131 ”£36 133 13a 1411 34 35 w a? 3? 33 as @9111 139 111:1 141 113 145 1413- 1-1? 92 1113 Q3 e4 {15 95 13.7.

BP, blood pressure * The 90th percentile is 1.28 SD, 95111 percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean.

Blood Pressure Levels for Girls by Age and Height Percentile Systoiic B'P (mml-ig) Diastolic BP tmml—ig} (- iile vef He§§ht -) (- Perceafiie of Heflgiat -) Age Perifile Wear) ‘3' 5111 1011'! 25th 58111 "£51.11 911111 9511’! 5133 111133 251211 50":11 75111 90m 95111 11.1 5131?} 98 99 181] 1132 1113 1134 195 59 59 5‘51 61} 61 62 62 9121121 112 112 114 115 115 118 113 73 T3 7'3 ?4 1'5 ?6 75 95111 116 116 117 119 12B 121 122 77 77" 77 78 79 89 80 991.11 123 123 125 126 12? 129 125! 81-1 84 85 85 36 87 88 11 5011?} 1139 101 102 103 1135 195 1131? 61} E9 69 51 62 63 63 901??! 114 114 116 117' 113 119 1213 74 74 7’4 75 713 77 7? 95111 113 ms; 119 121 122 123. 124 78 78 78 7Q 51} E1 E11 991151 125 125 126 128 129 131] 131 85 85 86 37 37 88 8 9 12 51311-1 11122 1133 104 1115 1Q? 1138 1139 61 51 61 52 63 54 611 913111 115 116 117 113 121} 121 122 7’5 75 75 76 7? 78 73 951171 1 19 121} 121 123 124 125 125 79 79' 79 3E} 81 82 82 991.11 12? 127 12B 139 131 132 133 85 85 87 88 813 89 9'1} 13 5131.11 1114 1615 1‘06 167 1139 110 111} 52 62 62 53 64 65 65 911111: 117 118 119 121 122 123 124 1’6 T6 78 7"? Y8 7Q 1'9 95111 121 122 1,23 124 126 127 128 80 80 813 31 82 83 83 9131.1“: 128 129 130 132 133 134 135 87' 87 88 BE} 89: 90 91 14 51311“: ”1136 1 [16 1D?" 1139 110 111 112 63 53‘ 53 621 65 ‘56 BS 911111 '1 19 121} 1.21 122 124 125 125 7? 77 77 78-1 72 BE} 81} 95111 123 123 125 128 127 129 129 31 81 :81 32 83 84 9911': 1.311 131 132 133 135 136 136 BE 83 89 9E} 90 £11 92 511111 113? me 109 11513 111 1133 113 64 54 64 65 66 67 E7 911111 120 121 1 22 123 125 125 127 78 BB 178 79 813 81 31 95111 124 125 125 121‘Y 129 1311 131 B2 82 82 33 3'4 85 85 99111 131 132 133 134 136 137 133 89 89 {98 Q1 91 92 93 16 51.11151 1138 1138 110 111 112 114 114 64 84 65 156 55 61' 58 910111 121 122 123 12-1 126 127 128 ?E ?8 7'9 BI} 31 B1 32 9511‘; 12:5 125 127' 128 130 131 132 82 82 83 34 8.5 85 E18 991131 132 133 134 135 137 138 139 91) 91] 913 $11 92 93 93 1? 50111 108 1139 110 111 113 114 115 64 55 55 66 6? 6? 63 90121 122, 122 123 125 126 127 128 TB 79 3’9 83 31 B1 82 951111 125 126 127 129 130 131 132 32 E3 83 8:11 85 85 8E 9911?: 133 133 134 136 131’ 133 139 $313 90 91 91 92 93 §3 BP, blood pressure * The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. ix Tanner stage l Tanner puberty stage classification l I Classification of sex maturity stages in girls I P2 Sparse, lightly pigmented, straight, %2 Breast and a elevated as small medial border of labia mound; r diameter increased P3 Darker, beginning to curl, increased B3 Breast and areola enlarged, no contour amount separation P4 Coarse, curly, abundant but amount B4 Areola and papilla form secondary mound less than in adult P5 Adult feminine triangle, spread to B5 ; nipple projects, areola part of medial surface of thighs general breast contour Classification of sex maturity stages in boys I P4 Resembles adult type, but less in T4 Larger, scrotum dark quantity; coarse, curly P5 Adult distribution, spread to medial Adult size surface of thighs

Claims (14)

Claims

1. Use of lixisenatide and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating pediatric patients suffering from type 2 es mellitus.

2. Use according to claim 1, wherein the lixisenatide and/or the pharmaceutically acceptable salt thereof is to be administered with metformin and/or a pharmaceutically able salt thereof as an add-on therapy.

3. Use according to claim 2, wherein metformin and/or the pharmaceutically acceptable salt thereof is formulated to be orally administered..

4. Use according to any one of the preceding claims, wherein the pediatric patient has an age of at least 10 years.

5. Use according to any one of the preceding claims, n the pediatric has an age of less than 18 years.

6. Use according to any one of the ing claims, wherein the type 2 diabetes mellitus has been diagnosed at least three months.

7. Use according to any one of the ing claims, wherein the type 2 diabetes mellitus is not adequately lled by metformin monotherapy, by basal insulin monotherapy or by a combination of metformin and a basal insulin.

8. Use according to any one of the preceding claims, wherein the pediatric patient is obese.

9. Use according to any one of the ing claims, wherein the pediatric patient has a body mass index of at least 30 kg/m2 or at least 31 kg/m2.

10. Use according to any one of the preceding claims, wherein the medicament is to be stered about 30 s before breakfast.

11. Use according to any one of the preceding claims, wherein at the onset of treatment with lixisenatide or/and the pharmaceutically acceptable salt 18464999_1 (GHMatters) P43144NZ00 thereof, the patient has a g plasma glucose concentration of at least 8 mmol/L or at least 8.5 mmol/L.

12. Use according to any one of the preceding claims, wherein at the onset of treatment with lixisenatide or/and the pharmaceutically acceptable salt thereof, the patient has a 2 hours postprandial plasma glucose concentration of at least 11.1 mmol/L or at least 12 mmol/L.

13. Use according to any one of the preceding claims, wherein at the onset of treatment with lixisenatide or/and the pharmaceutically acceptable salt thereof, the t has a glucose excursion of at least 3 , wherein the glucose excursion is the difference of the 2 hours postprandial plasma glucose concentration and plasma glucose concentration 30 s prior to a meal test.

14. Use according to any one of the preceding claims, wherein at the onset of treatment with lixisenatide or/and the ceutically acceptable salt thereof, the patient has a HbA1c value of at least about 7 %, at least about 7.5 %, at least about 8 %, at least about 8.5 %, at least about 8.65 %, or at least about 9%. 18464999_1 (GHMatters) P43144NZ00