WO2003066084A1 - Utilisation d'un compose glp-1 dans le traitement de patients gravement atteints - Google Patents

Utilisation d'un compose glp-1 dans le traitement de patients gravement atteints Download PDF

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Publication number
WO2003066084A1
WO2003066084A1 PCT/DK2003/000061 DK0300061W WO03066084A1 WO 2003066084 A1 WO2003066084 A1 WO 2003066084A1 DK 0300061 W DK0300061 W DK 0300061W WO 03066084 A1 WO03066084 A1 WO 03066084A1
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glp
patient
compound
cipnp
use according
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PCT/DK2003/000061
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English (en)
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Lotte Bjerre Knudsen
Johan Selmer
Kristian Tage Hansen
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Novo Nordisk A/S
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Priority to AU2003203146A priority Critical patent/AU2003203146A1/en
Publication of WO2003066084A1 publication Critical patent/WO2003066084A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to methods for prevention, treatment and/or cure of critically ill patients. More specifically, the methods and uses of the invention pertains to administration of a GLP-1 compound or a pharmaceutical medicament comprising a GLP-1 compound to critically ill patients. Furthermore, the present invention relates to a method for marketing GLP-1 compounds and to advertising media used for disseminating information.
  • CIPNP Crohn's disease
  • Electrophysiologi- cat examination is necessary to establish the diagnosis (Bolton CF. 1999 Acute Weakness. In: Oxford Textbook of Critical Care; Eds. Webb AR, Shapiro MJ, Singer M, Suter PM; Oxford Medical Publications, Oxford UK; pp. 490-495). This examination will reveal a primary axonal degeneration of first motor and then sensory fibers. Phrenic nerves are often involved. Acute and chronic denervation has been confirmed in muscle biopsies of this condition.
  • SIRS sepsis or SIRS
  • recovery from and/or prevention of the CIPNP can be expected. This will occur in a matter of weeks in mild cases and in months in more severe cases. In other words, the presence of CIPNP can delay the weaning and rehabilitation for weeks or months.
  • Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesised i.a. in the L-cells in the distal ileum, in the pancreas and in the brain. GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. Processing of preproglucagon to give GLP-1 (7-36)-amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells. The fragments GLP-1 (7-36)-amide and GLP-1 (7-37) are both glucose-dependent insulinotropic agents.
  • Exendin-4 is a 39 amino acid residue pep- tide isolated from the venom of Heloderma horridum, and this peptide shares 52% homology with GLP-1.
  • Exendin-4 is a potent GLP-1 receptor agonist which has been shown to stimulate insulin release and ensuing lowering of the blood glucose level when injected into dogs.
  • the group of GLP-1 (1-37), exendin-4(1-39), certain fragments thereof, analogs thereof and derivatives thereof, (hereinafter designated GLP-1 compounds) are potent insulinotropic agents.
  • GLP-1 compounds are also glucose-dependent in their action, i.e. they normalize hypergly- cemia but as blood glucose concentration decreases their activity attenuates so that the risk of hypoglycemic events are eliminated or greatly reduced as compared to the conventional treatment with insulin.
  • This lack of severe side effect from overdosing GLP-1 compounds make them very well suited to the therapeutic application within ICU.
  • the density of intense monitoring and multiple treatments of patients in ICU makes it highly advantageous that the strict control of the blood glucose level is simple and void of risks for hypoglycaemic events.
  • This invention is based on the discovery that critical illness in a patient and/or CIPNP can be prevented, treated or cured, at least to a certain extent, by controlling glucose metabolism during said critical illness by applying intensive treatment with a GLP-1 compound. Blood glucose level is kept below an upper limit which is about 110 mg/dL, about
  • blood glucose level is clamped within a range where the lower limit can be selected to be about 60, about 70 or about 80 mg/dL and the upper limit can be selected to be about 110, about 120 or about 130 mg/dL, more specifically to the normal range (i.e., from about 80 to about 110 mg/dL).
  • the physician will be able to decide exactly which upper and lower limits to use.
  • the range is from about 60 to about 130, preferably, from about 70 to about 120, more preferred, from about 80 to about 110 mg/dL. ).
  • the skilled art worker will be able to determine the dosage of GLP-1 compound without risking to induce a hypoglycaemic event because GLP-1 compounds have a glucose-dependent action where insulin release is attenuated at lower blood glucose concentrations.
  • One object of the present invention is to provide a treatment or cure of a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to increase the survival rate of critically ill patients and/or CIPNP patients and/or potential CIPNP patients.
  • Another object of the present invention is to provide a treatment or cure that reduces the time where a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient is hospitalized.
  • Another object of the present invention is to prevent that a patient becomes critically ill or develops CIPNP.
  • Another object of the present invention is to prevent, treat or cure SIRS in a patient.
  • Another object of the present invention is to prevent or reduce the likelihood of a pa- tient suffering from bacteraemia, septicaemia and/or septic shock during hospitalization.
  • Another object of the present invention is to prevent or reduce the likelihood that a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient acquires an infectious disease.
  • Another object of the present invention is to prevent or reduce the likelihood that a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient acquires an infectious disease with a mortal outcome.
  • Another object of the present invention is to provide a treatment or cure that reduces mortality, duration of hospitalization, frequency of bacteraemia, frequency of septi- caemia, frequency of septic shock, need for dialysis, and/or need for ventilatory support in a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce the risk or likelihood from multiple organ failure with a proven septic focus on post-mortem examination in a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce mortality, for example, in- hospital mortality, in a critically ill patient and/or in a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce morbidity, for example, in- hospital morbidity, in a critically ill patient and/or in a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce the likelihood of disturbed kidney function parameters in a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce the likelihood of hyper- bilirubinemia in a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce the likelihood for blood stream infections in a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce the likelihood of disturbance in markers of inflammations and/or inflammatory responses in a critically ill patient, and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to reduce the amount of red cell transfu- sion to a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to prevent or reduce the amount of ultimately futile intensive care to a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Another object of the present invention is to protect a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient from cholestasis.
  • Another object of the present invention is to reduce the need for invasive treatment in a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • GLP-1 compounds are provided for use in the prevention, treatment or cure of a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • This invention demonstrates that controlling blood glucose levels within the above range, for example, within normal limits (about 80 to about 110 mg/dL) in a critically ill patient or in a chronic ill patient can be used to significantly reduce the incidence of critical illness in a patient and/or CIPNP and to lengthen the time free of critical illness in a patient and/or CIPNP in a patient that do develop this problem.
  • the invention provides a use of a GLP-1 compound for preventing or reducing the likelihood of a patient suffering from bacteraemia, septicaemia and/or septic shock during hospitalization.
  • the invention also provides a use of a GLP-1 compound for preventing or reducing the likelihood that a critically ill patient and/or a CIPNP patient and/or a potentially CIPNP patient acquires an infectious disease.
  • the invention also provides a use of a GLP-1 compound for preventing or reducing the likelihood that a critically ill patient and/or a CIPNP patient and/or a potentially CIPNP pa- tient dies due to an infection.
  • the invention also provides a use of a GLP-1 compound for reducing the rate of infection with mortal outcome in critically ill patients and/or CIPNP patients and/or potentially CIPNP patients.
  • blood glucose levels are controlled by treatment with GLP-1 compounds.
  • GLP-1 compounds it will be clear for the man skilled in the art that also other agonists of the GLP-1 receptor, prodrugs thereof and their physiologically tolerated salts can be used to obtain the same outcome.
  • systemic inflammatory response syndrome refers to the uncontrolled disease process which ensues an initial insult and which gives rise to a multisystem disturbance secondary to inflammatory mediators released during shock.
  • serpsis refers to "SIRS”, as described above, which is particularly caused by an infectious insult leading to the initial shock phase.
  • inflammatory cells such as TNFs, interleukins, bradykinins etc.
  • insulin receptor type tyrosine kinase refers to a post- receptor signal transduction pathway involved in the insulin signaling.
  • endoneural edema refers to swelling of the neuronal cells.
  • GLP-1 compound refers to GLP-1 (1-37), exendin-4(1-
  • Insulinotropic fragments of GLP-1 (1-37) are insulinotropic peptides for which the entire sequence can be found in the sequence of GLP-1 (1-37) and where at least one terminal amino acid has been deleted.
  • Examples of insulinotropic fragments of GLP-1 (1-37) are GLP-1 (7-37) wherein the amino acid residues in positions 1-6 of GLP-1 (1-37) have been deleted, and GLP-1(7-36) where the amino acid residues in position 1-6 and 37 of GLP-1(1- 37) have been deleted.
  • Examples of insulinotropic fragments of exendin-4(1-39) are exendin- , 4(1-38) and exendin-4(1-31).
  • the insulinotropic property of a compound may be determined by in vivo or in vitro assays well known in the art. For instance, the compound may be admin- istered to an animal and monitoring the insulin concentration over time.
  • Insulinotropic analogs of GLP-1 (1-37) and exendin-4(1-39) refer to the respective molecules wherein one or more of the amino acids residues have been exchanged with other amino acid residues and/or from which one or more amino acid residues have been deleted and/or from which one or more amino acid residues have been added with the proviso that said analogue either is insulinotropic or is a prodrug of an insulinotropic compound .
  • Examples of insulinotropic analogs of GLP-1 (1-37) are e.g.
  • insulinotropic analogs of ex- endin-4(1-39) is Ser 2 Asp 3 -exendin-4(1-39) wherein the amino acid residues in position 2 and 3 have been replaced with serine and aspartic acid, respectively (this particular analog also being known in the art as exendin-3), and a fusion protein between exendin-4(1-39) and hu- man serum albumin.
  • Insulinotropic derivatives of GLP-1 (1-37), exendin-4(1-39) and analogs thereof are what the person skilled in the art considers to be derivatives of these peptides, i.e. having at least one substituent which is not present in the parent peptide molecule with the proviso that said derivative either is insulinotropic or is a prodrug of an insulinotropic compound.
  • substituents are amides, carbohydrates, alkyl groups and lipophilic substituents.
  • Examples of insulinotropic derivatives of GLP-1 (1 -37), exendin-4(1 -39) and analogs thereof are GLP-1 (7-36)-amide, Arg 34 , Lys 26 (N ⁇ -( ⁇ -Glu(N ⁇ -hexadecanoyl)))-GLP-1(7- 37) and Tyr 31 -exendin-4(1-31)-amide.
  • GLP-1 (1-37), exendin-4(1-39), insulinotropic fragments thereof, insulinotropic analogs thereof and insulinotropic derivatives thereof are described in WO 98/08871, WO 99/43706, US 5424286 and WO 00/09666.
  • stable GLP-1 analog/derivative refers to a GLP-1 (1-37) analog or derivative thereof which exhibits an in vivo plasma elimination half-life of at least 10 hours in man, as determined by the method described below. Examples of stable derivatives of GLP-1 analogs can be found in WO 98/08871 , WO 99/43706 and WO 02/46227.
  • the method for determination of plasma elimination half-life of a compound in man is :
  • the com- pound is dissolved in an isotonic buffer, pH 7.4, PBS or any other suitable buffer.
  • the dose is injected peripherally, preferably in the abdominal or upper thigh.
  • Blood samples for determination of active compound are taken at frequent intervals, and for a sufficient duration to cover the terminal elimination part (e.g. Pre-dose, 1 , 2, 3, 4, 5, 6, 7, 8, 10, 12, 24 (day 2), 36 (day 2), 48 (day 3), 60 (day 3), 72 (day 4) and 84 (day 4) hours post dose).
  • Determination of the concentration of active compound is performed as described in Wilken et al., Diabetolo- gia 43(51 ):A143, 2000.
  • Derived pharmacokinetic parameteres are calculated from the concentration-time data for each individual subject by use of non-compartmental methods, using the commercially available software WinNonlin Version 2.1 (Pharsight, Gary, NC, USA).
  • the terminal elimination rate constant is estimated by log-linear regression on the terminal log- linear part of the concentration-time curve, and used for calculating the elimination half-life.
  • stable exendin-4 analog/derivative refers to a exendin- 4(1-39) analog or derivative thereof which exhibits an in vivo plasma elimination half-life of at least 10 hours in man, as determined by the method described above.
  • Typical examples of stable exendin-4 analog/derivatives are exendin-4 compounds chemically modified by acyla- tion, PEGylation and fused to serum albumin or fragments thereof.
  • blood glucose regulator refers to any compound which is able to regulate the blood glucose level.
  • blood glucose regulators are insulin, insulin derivatives, insulin analogues, compounds that stimulate signal transduction mediated by an insulin receptor type tyrosine kinase in a cell, certain protein-tyrosine phosphatases (PTP's), other Type II antidiabetica, and other biologically active substances having insulin releasing action.
  • PTP's protein-tyrosine phosphatases
  • insulin refers to insulin from any species such as human insulin, porcine insulin, bovine insulin and salts thereof such as zinc salts and protamin salts.
  • insulin analogues refers to insulin wherein one or more of the amino acid residues have been exchanged with another amino acid residue and/or from which one or more amino acid residue has been deleted and/or from which one or more amino acid residue has been added with the proviso that said insulin analogue has a suffi- , cient insulin activity to lower the blood glucose level.
  • free fat cell assay any skilled art worker, for example, a physician, knows when and which dosages to administer of the insulin analogue.
  • insulin analogues examples include insulin aspart (i.e., Asp B28 human insulin), insulin lispro (i.e., Lys B28 ,Pro B29 human insulin), and insulin glargine (i.e., Gly ⁇ .Arg ⁇ Arg 832 human insulin).
  • insulin aspart i.e., Asp B28 human insulin
  • insulin lispro i.e., Lys B28 ,Pro B29 human insulin
  • insulin glargine i.e., Gly ⁇ .Arg ⁇ Arg 832 human insulin.
  • derivatives of insulin as used herein are what a skilled art worker generally considers derivatives, for example, insulin having one or more substituents not present in the parent insulin molecule. Also included in “derivatives of insulin” are derivatives of insulin analogs.
  • non-diabetic patient refers to a patient who has not been diagnosed as having diabetes.
  • a “critically ill patient” refers to a patient who has sustained or are at risk of sustaining acutely life- threatening single or multiple organ system failure due to disease or injury, a patient who is being operated and where complications supervene, and a patient who has been operated in a vital organ within the last week or has been subject to major surgery within the last week.
  • CIP critically ill patient
  • the term a “critically ill patient”, as used herein refers to a patient who has sustained or are at risk of sustaining acutely life-threatening single or multiple organ system failure due to disease or injury, or a patient who is being operated and where complications supervene.
  • a critically ill patient refers to a patient who has sustained or are at risk of sustaining acutely life- threatening single or multiple organ system failure due to disease or injury.
  • these definitions apply to similar expressions such as "critical illness in a patient” and a "patient is critically ill”.
  • ICU Intensive Care Unit
  • ICU Intensive Care Unit
  • ICU refers to the part of a hospital where critically ill patients are treated. Of course, this might vary from country to country and even from hospital to hospital and said part of the hospital may not necessary, officially, bear the name "Intensive Care Unit” or a translation or derivation thereof. Of course, the term “Intensive Care Unit” also covers a nursing home, a clinic, for example, a private clinic, or the like if the same or similar activities are performed there.
  • CIPNP Crohn's disease polyneuropathy
  • administration of a GLP-1 compound in combination with a second compound refers to the administration of the two compounds in overlapping time periods, i.e. the patient is treated with the GLP-1 compound at a time where said patient is also treated with the second compound or has been treated with the second compound until 24 hours prior to the start of administration of the GLP-1 compound.
  • administration of a GLP-1 compound in combination with a second compound is taking place unless the administration of the second compound is stopped at least 24 hours before the start of administration of the GLP-1 compound, irrespective of whether the two compounds are adminis- tered as separate pharmaceutical compositions.
  • medicament refers to a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.
  • GLP-1 agonist refers to a molecule, preferably GLP-1 or an analogue or a derivative thereof, or exendin or an analogue or a derivative thereof, or a non-peptidyl compound, which interacts with the GLP-1 receptor and induces the physiology- ical and pharmacological characteristics of the GLP-1 receptor.
  • a GLP-1 agonist binds to the GLP-1 receptor with an affinity constant Kp, below 1 ⁇ M, preferably below 100 nM. Methods for identifying GLP-1 agonists are described in WO 93/19175 (Novo Nordisk A/S).
  • GLP-1 agonist is also intended to comprise active metabolites and prodrugs thereof, such as active metabolites and prodrugs of GLP-1 or an analogue or a derivative thereof, or ex- endin or an analogue or a derivative thereof, or a non-peptidyl compound.
  • a "metabolite” is an active derivative of a GLP-1 agonist produced when the GLP-1 agonist is metabolized.
  • a “prodrug” is a compound which is either metabolized to a GLP-1 agonist or is metabolized to the same metabolite(s) as a GLP-1 agonist.
  • ICU intensive care unit
  • a special hospital unit for example a post operative ward or the like, which is capable of providing a high level of intensive therapy in terms of quality and immediacy.
  • Examples of a critically ill patient is a patient in need of cardiac surgery, cerebral surgery, thoracic surgery, abdominal surgery, vascular surgery, or transplantation, or a patient suffering from neurological diseases, cerebral trauma, respiratory insufficiency, abdomi- nal peritonitis, multiple trauma, severe burns, or CIPNP.
  • the glucose metabolism of a clinical ill patient may be controlled by clamping the blood glucose level within the ranges mentioned in connection with the present invention.
  • the skilled art worker for example, a physician, may do this using a GLP-1 compound.
  • the skilled art worker is able to find the pharmaceutically effective amount of the GLP-1 compound used and to determine how often it is to be administered (depending on the patients weight, gender, disease condition etc.).
  • the blood glucose level is kept within the ranges mentioned in connection with the present invention for as long a period of time as the patient is critically ill.
  • the blood glucose level is kept within the ranges mentioned in connection with the present invention as long as the patient is critically ill. Consequently, the blood glucose level is usually kept within the ranges mentioned in connection with the present invention for a period of time of more than about 8 hours, preferably more than about 24 hours, even more preferred more than about 2 days, especially more than about 4 days, and even more than about 7 days.
  • the blood glucose level is kept within the ranges mentioned in connection with the present invention after the patient (previously) considered as being critically ill has been transferred from the Intensive Care Unit to another part of the hospital or even after said patient has left the hospital.
  • a critical ill patient may be fed continuously, on admission with mainly intravenous glucose (for example, about 200 g to about 300 g per 24 hours) and from the next day onward with a standardised feeding schedule aiming for a caloric content up to between about 10 and about 40, preferably between about 20 and about 30, non- protein Calories/kg/24 hours and a balanced composition (for example, between about 0.05 and about 0.4, preferably between about 0.13 and about 0.26, g nitrogen/kg/24 hours and between about 20% and about 40% of non-protein Calories as lipids) of either total par- enteral, combined parenteral/enteral or full enteral feeding, the latter mode attempted as early as possible.
  • Other concomitant ICU therapy can be left to the discretion of attending physicians.
  • a critical ill patient may be fed, on the admission day, using, for example, a 20% glucose infusion and from day 2 onward by using a standardised feeding schedule consisting of normal caloric intake (for example, about 25-35 Calories/kg BW/24h) and balanced composition (for example, about 20%-40% of the non-protein Calories as lipids and about 1-2 g/kgBW/24h protein) of either total parenteral, combined parenteral/enteral or full enteral feeding, the route of administration of feeding depending on assessment of feasibility of early enteral feeding by the attending physician. All other treatments, including feeding regimens, were according to standing orders currently applied within the ICU.
  • the GLP-1 compound is GLP-1 (7-37), GLP-1 (7-36) amide, or an analog thereof or a derivative thereof.
  • GLP-1 compounds include, but are not limited to, Arg 26 -GLP-1(7-37); Arg 34 -GLP-1(7-37); Lys 36 -GLP-1 (7-37); Arg 26 ' 34 Lys 36 -GLP-1(7-37); Arg 26 ' 34 - GLP-1 (7-37); Arg ⁇ Lys ⁇ -GLP-l (7-37); Arg 26 Lys 36 -GLP-1 (7-37); Arg 34 Lys 36 -GLP-1 (7-37); Val 8 Arg 22 -GLP-1 (7-37); Met 8 Arg 22 -GLP-1 (7-37);Gly 8 His 22 -GLP-1 (7-37); Val 8 His 22 -GLP-1 (7- 37); Met 8 His 22 -GLP-1(7-37);His 37 -GLP-1(7-37); Gly 8 -GLP
  • the GLP-1 compound is a fusion protein between GLP-1 (7- 37), an analogue or a derivative thereof, and human serum albumin or a variant, e.g. frag- ment, thereof.
  • the GLP-1 compound is a fusion protein between GLP-1 (7- 37), an analogue or a derivative thereof, and human serum albumin or a variant, e.g. frag- ment, thereof.
  • the GLP-1 compound is a fusion protein between GLP-1 (7- 37), an analogue or a derivative thereof, and human serum albumin or a variant, e.g. frag- ment, thereof.
  • the GLP-1 compound is a fusion protein between
  • GLP-1 (7-37), an analogue or a derivative thereof, and the Fc portion of an immunoglobulin or a variant, e.g. fragment, thereof.
  • GLP-1 analogues and derivatives which can be used according to the present invention includes those referred to in WO 99/43705 (Novo Nordisk A/S), WO 99/43706 (Novo Nordisk A/S), WO 99/43707 (Novo Nordisk A/S), WO 98/08871 (Novo Nordisk A/S), WO 99/43708 (Novo Nordisk A/S), WO 99/43341 (Novo Nordisk A/S), WO 87/06941 (The General Hospital Corporation), WO 90/11296 (The General Hospital Corporation), WO 91/11457 (Buckley et al.), WO 98/43658 (Eli Lilly & Co.), EP 0708179-A2 (Eli Lilly & Co.), EP 0699686-A2 (Eli Lilly & Co.), WO 01/98331 (Eli Lilly & Co).
  • the GLP-1 compound is selected from exendin as well as analogs, derivatives, and fragments thereof, e.g. exendin-3 and exendin-4.
  • exendins as well as analogs, derivatives, and fragments thereof to be included within the present invention are those disclosed in WO 9746584, US 5424286 and WO 01/04156.
  • US 5424286 describes a method for stimulating insulin release with an exendin polypeptide.
  • WO 9746584 describes truncated versions of exendin peptide(s). The disclosed peptides increase secretion and biosynthesis of insulin, but reduce those of glucagon.
  • the GLP-1 compound is a fusion protein between exendin- 4(1-39), an analogue or a derivative thereof, and human serum albumin or a variant, e.g. fragment, thereof.
  • the GLP-1 compound is a fusion protein between exendin-4(1-39), an analogue or a derivative thereof, and the Fc portion of an immunoglobu- lin or a variant, e.g. fragment, thereof.
  • WO 01/04156 describes exendin-4 analogs and derivatives as well as the preparation of these molecules.
  • WO 02/46227 describes GLP-1 compounds which are exendin-4 fusion proteins and the preparation of these molecules.
  • GLP-1 compounds can be produced by appropriate derivatization of an appropriate peptide backbone which has been produced by recombinant DNA technology or by peptide synthesis (e.g. Merrifield-type solid phase synthesis) as known in the art of peptide synthesis and peptide chemistry.
  • the route of administration of GLP-1 compounds may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, buccal, pulmonal, transdermal or parenteral.
  • Medicaments or pharmaceutical compositions containing a GLP-1 compound may be administered parenterally to a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • Parenteral admini- stration may be performed by subcutaneous, intramuscular or intravenous injection by means of a syringe, optionally a pen-like syringe.
  • parenteral administration can be performed by means of an infusion pump.
  • a further option is a composition which may be a powder or a liquid for the administration of a GLP-1 compound in the form of a nasal or pulmonal spray.
  • the GLP-1 compound can also be administered transdermally, e.g. from a patch, optionally a iontophoretic patch, or transmucosally, e.g. bucally.
  • the above-mentioned possible ways to administer GLP-1 compounds are not considered as limiting the scope of the invention.
  • compositions containing GLP-1 compounds such as Arg 34 , Lys 26 (N ⁇ - ( ⁇ -Glu(N ⁇ -hexadecanoyl)))-GLP-1(7-37), may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19 th edition, 1995.
  • the injectable compositions of GLP-1 compounds can be prepared using the conventional techniques of the pharmaceutical industry which involves dissolving and mixing the ingredients as appropriate to give the desired end product. According to one procedure, e.g. Arg 34 , Lys 26 (N ⁇ -( ⁇ -Glu(N ⁇ -hexadecanoyl)))-GLP-1 (7-
  • isotonic agents sodium chloride, mannitol and glycerol.
  • preservatives examples include phenol, m-cresol, methyl p-hydroxybenzoate and benzyl alcohol.
  • solutions containing a GLP-1 compound may also contain a surfactant in order to improve the solubility and/or the stability of the peptide.
  • the GLP-1 compound is provided in the form of a composition suitable for administration by injection.
  • a composition can either be an injectable solution ready for use or it can be an amount of a solid composition, e.g. a lyophilised product, which has to be dissolved in a solvent before it can be injected.
  • the injectable solution preferably contains not less than about 0.1 mg/ml, typically from 0.1 mg/ml to 10 mg/ml, such as from 1 mg/ml to 5 mg/ml of GLP-1 compound.
  • GLP-1 compounds such as Arg 34 , Lys 26 (N ⁇ -( ⁇ -Glu(N ⁇ -hexadecanoyl)))-GLP-1(7-37) can be used in the treatment of all critically ill patients and/or CIPNP patients and/or potential CIPNP patients.
  • the optimal dose level for any patient (effective amount) will depend on the history and state of that particular patient to be treated. The person skilled in the art, e.g. a physician, will know how to determine the optimal dose level in order to control the blood glucose level within intervals mentioned herein.
  • the present GLP-1 compounds may be administered in combination with one or more anti- hypertensive agents.
  • antihypertensive agents examples include ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, alatriopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, ni- modipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin.
  • ACE angiotensin converting enzyme
  • the present GLP-1 compounds may be administered in combination with a compound selected from human growth hormone, growth hormone releasing compounds, a growth factor such as prolactin or placental lactogen, FVII and other factors in the blood clotting cascade.
  • a compound selected from human growth hormone, growth hormone releasing compounds, a growth factor such as prolactin or placental lactogen, FVII and other factors in the blood clotting cascade may be administered in combination with a compound selected from human growth hormone, growth hormone releasing compounds, a growth factor such as prolactin or placental lactogen, FVII and other factors in the blood clotting cascade.
  • the present invention also relates to a method of marketing a GLP-1 compound, said method comprising the dissemination of information about the indications, utilities and benefits of a GLP-1 compound or a pharmaceutical composition comprising a GLP-1 compound, said indications, utilities, benefits and GLP-1 compounds being according to the present invention.
  • Another method of marketing a GLP-1 compound according to the present invention is to support a speaker disseminating information about the indications, utilities and benefits of a GLP-1 compound or a pharmaceutical composition comprising a GLP-1 compound, said indications, utilities, benefits and GLP-1 compounds being according to the present invention. Examples are supporting a speaker at a symposium or congress within the fields of medicine, ICU and/or health care economics.
  • the present invention also relates to advertising media to disseminate information about the indications, utilities and benefits of a GLP-1 compound or a pharmaceutical composition comprising a GLP-1 compound, said indications, utilities, benefits and GLP-1 compounds being according to the present invention.
  • advertising media and material and information media and material is a brochure, pamphlet, or packaging material which is used for the customer package such as the outer box, the inner box, or a blister- pack, any printed material/leaflet supplied with the medicament such as a package insert, a patient leaflet, or patient information, a label, a web site, a movie, an advertising movie, a video, a DVD, a CD-ROM and the like.
  • An example of a brochure according to the present invention is a brochure in which it is stated (or suggested) that insulin can be used to treat critically ill patients and/or CIPNP patients, for example in an ICU.
  • An advertising medium according to the present invention can have the following text:
  • LIFE SAVING TREATMENT In order to save life, it is important that the blood glucose level of a critically ill patient is kept within the range from about 80 to about 110 mg/dL. This can be done with no risk of hypoglycaemic event by using NN2211 from Novo Nordisk A/S. More information will be available from www.novonordisk.com.
  • the advertising media according to the present invention are preferably presented or distrumped to physicians working in an ICU and persons responsible for the budget in an ICU.
  • the present invention relates to a use of a GLP-1 compound for the manufacture of a medicament for treatment or cure of a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient.
  • the present invention relates to the novel uses described herein, wherein the treatment or cure increases the survival rate of critically ill pa- tients and/or CIPNP patients and/or potential CIPNP patients.
  • the present invention relates to the novel uses described herein, wherein the treatment or cure reduces the time where a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient is hospitalized.
  • the present invention relates to the novel uses described herein, wherein the patient is hospitalized in an ICU.
  • the present invention relates to a use of a GLP-1 compound for the manufacture of a medicament for preventing that a patient becomes critically ill or develops CIPNP. According to a further aspect, the present invention relates to a use of a GLP-1 compound for the manufacture of a medicament for prevention, treatment or cure of SIRS in a patient.
  • the present invention relates to a use of a GLP-1 com- pound for the manufacture of a medicament for preventing or reducing the likelihood of a patient suffering from bacteraemia, septicaemia and/or septic shock during hospitalization.
  • the present invention relates to the novel uses described herein, where the hospitalization is in an ICU.
  • the present invention relates to the novel uses described herein, wherein the patient is selected from a critically ill patient, a CIPNP patient, a potential CIPNP patient, a SIRS patient and a potential SIRS patient.
  • the present invention relates to a use of a GLP-1 compound for manufacturing a medicament for preventing or reducing the likelihood that a critically ill patient and/or a CIPNP patient and/or a potential CIPNP patient acquires an infec- tious disease.
  • the present invention relates to the novel uses described herein, wherein the infectious disease has a mortal outcome.
  • the present invention relates to a use of a GLP-1 compound for manufacturing a medicament for preventing or reducing the likelihood that a criti- cally ill patient and/or a CIPNP patient and/or a potential CIPNP patient dies due to an infection.
  • the present invention relates to a use of a GLP-1 compound for manufacturing a medicament for reducing the rate of infection with mortal outcome in critically ill patients and/or CIPNP patients and/or potential CIPNP patients in an ICU.
  • the present invention relates to the novel uses described herein, wherein the treatment or cure reduces mortality, duration of hospitalization, frequency of bacteraemia, frequency of septicaemia, frequency of septic shock, need for dialysis, and/or need for ventilatory support in said patient.
  • the present invention relates to a use of a GLP-1 compound for the manufacture of a medicament to treat a critically ill patient and/or a CIPNP- patient and/or a potential CIPNP-patient so that the patient is no longer in need of vital organ system support or to treat a critically ill patient and/or a CIPNP-patient and/or a potential CIPNP-patient so that it is considered sufficient for the patient to receive at least about two third of the caloric need through the normal enteral route to reduce the risk or likelihood from multiple organ failure, to reduce the risk or likelihood from multiple organ failure with a proven septic focus on post-mortem examination, to reduce mortality, for example, in-hospital mortality, to reduce the use of mechanical ventilatory support, to reduce the likelihood of renal replacement therapy and/or renal failure, to reduce the likelihood of disturbed kidney function parameters, to reduce the likelihood of hyperbilirubinemia, to reduce the likelihood for blood stream infections, to reduce the likelihood of disturbance in markers of inflammations and/or inflammatory responses, to reduce
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is a derivative of GLP-1 (7-36)-amide or GLP-1 (7-37) which comprises a lipophilic substituent.
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is Arg 34 , Lys 26 (N ⁇ -( ⁇ -Glu(N ⁇ -hexadecanoyl)))- GLP-1(7-37).
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is selected from the group consisting of Gly 8 -GLP-1(7-36)-amide, Gly 8 -GLP- 1(7-37), Val 8 -GLP-1 (7-36)-amide, Val 8 -GLP-1 (7-37), Val 8 Asp 22 -GLP-1(7-36)-amide, Val 8 Asp 22 -GLP-1(7-37) , VaPGIu ⁇ -GLP-l (7-36)-amide , Val 8 Glu 22 -GLP-1(7-37), Val 8 Lys 22 -GLP-1 (7-36)-amide, Val 8 Lys 22 -GLP-1(7-37), Val 8 Arg 22 - GLP-1(7-36)-amide, Val 8 Arg 22 -GLP-1 (7-37), Val 8 His 22 -GLP-1(7-36)-amide, Val 8 His 22 -GLP- 1 (7-37), ana
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is selected from the group consisting of Arg 26 -GLP-1(7-37); Arg ⁇ -GLP-I (7-37); Lys 36 -GLP-1(7-37); Arg 26 ' 34 Lys 36 -GLP-1(7-37); Arg 26 ' 34 - GLP-1(7-37); Arg ⁇ Lys ⁇ -GLP-l ⁇ ); Arg 26 Lys 36 -GLP-1(7-37); Arg 34 Lys 36 -GLP-1(7-37); Val 8 Arg 22 -GLP-1 (7-37); Met 8 Arg 22 -GLP-1 (7-37);Gly 8 His 22 -GLP-1 (7-37); Val 8 His 22 -GLP-1 (7- 37); Met 8 His 22 -GLP-1(7-37);His 37 -GLP-1(7-37); Gly 8 -GLP-1 (7-37); Val 8 -GLP-1 (7-37); Val 8
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is a stable GLP-1 analog/derivative. According to a further embodiment, the present invention relates to the novel uses described herein, wherein the GLP-1 compound is exendin-4 or an analogue thereof or a derivative thereof.
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is a stable exendin-4 analog/derivative. According to a further embodiment, the present invention relates to the novel uses described herein, wherein the GLP-1 compound is to be administered parenterally.
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is administered by injection. According to a further embodiment, the present invention relates to the novel uses described herein, wherein the GLP-1 compound is administered by infusion or drip.
  • the present invention relates to the novel uses described herein, wherein the dosage of GLP-1 compound is from about 0.5 ⁇ g/kg/day to about 20 ⁇ g/kg/day. According to a further embodiment, the present invention relates to the novel uses described herein, wherein the dosage of GLP-1 compound is from about 0.1 g/kg/day to about 2 / g/kg/day.
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is used such that the blood glucose level is kept below an upper limit which is about 110 mg/dL, about 120 mg/dL or about 130 mg/dL.
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is used such that the blood glucose level is kept within a range where the lower limit is about 60 mg/dL, about 70 mg/dL or about 80 mg/dL and the upper limit is about 110 mg/dL, about 120 mg/dL or about 130 mg/dL, pref- erably in the range of 80 to about 110 mg/dL.
  • the present invention relates to the novel uses described herein, wherein the GLP-1 compound is used such that the blood glucose level is kept within a range from about 60 mg/dL to about 130 mg/dL, preferably from about 70 mg/dL to about 120 mg/dL, more preferred from about 80 mg/dL to about 110 mg/dL.
  • the present invention relates to the novel uses described herein, wherein the blood glucose level is kept within the specified range for a period of more than about 8 hours, preferably for more than about 24 hours, more preferred for more than about 2 days, even more preferred for more than about 4 days, and even more preferred for more than about 7 days.
  • the present invention relates to the novel uses described herein, wherein a second blood glucose regulator is used.
  • the present invention relates to the novel uses described herein, wherein the second blood glucose regulator is selected from insulin, insulin analogs, insulin derivatives, insulin secretagogues, insulin compounds that stimulate signal transduction mediated by an insulin receptor type tyrosine kinase in a cell, protein-tyrosine phosphatases and Type II antidiabetica.
  • the second blood glucose regulator is selected from insulin, insulin analogs, insulin derivatives, insulin secretagogues, insulin compounds that stimulate signal transduction mediated by an insulin receptor type tyrosine kinase in a cell, protein-tyrosine phosphatases and Type II antidiabetica.
  • the present invention relates to the novel uses described herein, wherein the second blood glucose regulator is selected from insulin, an insulin analog, an insulin derivative, a GLP-1 compound and an orally administered blood glucose regulator.
  • the present invention relates to the novel uses described herein, wherein treatment, curing or prevention is performed by administering an effective amount of the second blood glucose regulator. According to a further aspect, the present invention relates to administration of a
  • GLP-1 compound in combination with one or more antihypertensive agents for example ⁇ - blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (an- giotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, alatriopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ -blockers such as doxazosin, urapidil, prazosin and terazosin.
  • ⁇ -blockers such as alprenolol, atenolol, timolol, pindo
  • the present invention relates to administration of a GLP-1 compound in combination with a compound selected from human growth hormone, growth hormone releasing compounds, a growth factor such as prolactin or placental lacto- gen, FVII and other factors in the blood clotting cascade.
  • the present invention relates to the novel uses described herein, wherein the patient is a non-diabetic patient.
  • the present invention relates to the novel uses described herein, wherein the patient is a human. According to a further embodiment, the present invention relates to the novel uses described herein, wherein the patient is in need of cardiac surgery, cerebral surgery, thoracic surgery, abdominal surgery, vascular surgery, or transplantation, or a patient suffering from neurological diseases, cerebral trauma, respiratory insufficiency, abdominal peritonitis, multiple trauma, severe burns, or CIPNP. According to a further embodiment, the present invention relates to the novel uses described herein, wherein the patient is fed parenterally.
  • the present invention relates to the novel uses described herein, wherein the patient receives at least about one third of the caloric need through the normal enteral route, preferably at least about half of the caloric need through the normal enteral route, most preferable at least about two third of the caloric need through the normal enteric route.
  • the present invention relates to the novel uses described herein, wherein treatment, curing or prevention is performed by administering an effective amount of the GLP-1 compound.
  • the present invention relates to the use of a GLP-1 compound for the treatment or cure of critically ill patients and/or CIPNP patients and/or potential CIPNP patients.
  • the present invention relates to the novel uses de- scribed herein, wherein the treatment or cure comprises a pharmaceutically effective composition comprising the GLP-1 compound.
  • the present invention relates to the novel uses described herein, wherein said use is to attain the clinical benefits mentioned in any one of the preceding claims.
  • the present invention relates to a kit of parts compris- ing a medicament wherein is a GLP-1 compound and an insert label stating the use of said medicament for treating critically ill patients within an ICU.
  • the present invention relates to a method of marketing a GLP-1 compound, said method comprising the dissemination of information about the indications, utilities and benefits of a GLP-1 compound or a pharmaceutical composition comprising a GLP-1 compound, said indications, utilities, benefits and GLP-1 compounds being described in the aspects, embodiments and claims of the present invention.
  • the present invention relates to the novel method described herein, wherein the information is disseminated by means of printed material, oral presentation or electromagnetic signals, such as via internet, telephone, television, radio or computer.
  • the present invention relates to the novel methods described herein, wherein the information is disseminated to physicians and/or persons responsible for health care budgets, preferably to physicians working in an ICU and persons responsible for an ICU budget.
  • the present invention relates to an advertising medium to disseminate information about the indications, utilities and benefits of a GLP-1 compound or a pharmaceutical composition comprising a GLP-1 compound, said indications, utilities, benefits and GLP-1 compounds being described in the uses of the present invention.
  • the present invention relates to the novel advertising media described herein, wherein said advertising media are selected from the group consisting of a brochure, pamphlet, prospectus, videotape, DVD disk and CD disk.
  • NN2211 In a randomized, double-blind, placebo-controlled, crossover study the effect of NN2211 on beta cell sensitivity to glucose was tested in 10 subjects with type 2 diabetes following a single dose of NN2211 (7.5 ⁇ g/kg) or placebo. Using a graded glucose infusion protocol with plasma glucose levels matched over the range of 5 to 12 mmol/L beta cell sensitivity was assessed. Insulin secretion rates (ISR) were estimated by deconvolution of circulating C-peptide concentrations. Findings were compared to responses of 10 healthy, nondiabetic volunteers to the same glucose infusion protocol.
  • ISR Insulin secretion rates
  • NN2211 Compared to placebo, a single dose of NN2211 increased insulin and C-peptide levels, increased ISR area under the curve (AUC) (1130 ⁇ 150 vs. 668 + 106 pmol/kg; p ⁇ 0.001), and increased slope of ISR vs. plasma glucose (1.26 ⁇ 0.36 vs. 0.54 ⁇ 0.18 pmo iJ(min*mmol*kg); p ⁇ 0.014), to values similar to nondiabetic controls who did not receive the drug (ISR AUC 1206 ⁇ 99; slope of ISR vs. plasma glucose 1.44 ⁇ 0.18). No hypo- glycemic events occurred. Importantly insulin secretion was comparable to the non-diabetic controls at low glucose levels.
  • a single dose of the long-acting GLP-1 derivative, NN2211 improves beta cell sensitivity to physiological hyperglycemia in type 2 diabetes patients, and confirms that NN2211 provides a glucose-dependent insulin secretion.
  • NN2211 improves glyceamic control in patients with type 2 diabetes, and furthermore, the low incidence of any hypoglycaemic event also in comparison to glimepiride (that acts by stimulating insulin secretion), corroborates the glucose dependent insulin secretion of NN2211 described in example 1 , and suggests its therapeutic advantage on the side effect profile as compared to exogenous insulin administration that is known to be associated with hypoglycaemia if dosing is not carefully titrated. Furthermore, the once daily dosing regimen of NN2211 would be a therapeutic advantage compared to a carefully titrated insulin administration regimen.
  • APACHE-II acute Physiology and Chronic Health Evaluation
  • TISS-28 simplified Therapeutic Intervention Scoring System
  • APACHE II and TISS scores are calculated daily from ICU admission to discharge or death. Continuous blood samples for glucose, clinical chemistry, hematology and markers of inflammation, blood culture (if appropriate).
  • EMG electromyography
  • the primary endpoint would be death from all causes during intensive care. Secondary outcome measures are in-hospital mortality, incidence of prolonged intensive care dependency and need for ICU re-admission, need for vital organ system support comprising mechanical ven- tilatory support, renal replacement therapy (continuous or intermittent hemofiltration or dialysis), inotropic or vasopressor support, incidence of critical illness polyneuropathy, the degree of inflammation, incidence of blood stream infections and use of antibiotics, transfusion requirements and incidence of hyperbilirubinemia. Furthermore, use of intensive care resources should be analysed by cumulative TISS scores.
  • patients are defined as 'dischargable from ICU' when they were no longer in need of vital organ system support and received at least 2/3rd of the caloric need through the normal enteral route or earlier when actually sent to a ward.

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Abstract

L'invention concerne l'utilisation d'un médicament constituant un traitement de survie pour des patients gravement atteints ou pour des patients souffrant du syndrome de réponse inflammatoire systémique (SIRS). L'invention concerne également une méthode thérapeutique. Le médicament selon l'invention contient un composé GLP-1 qui régule de manière efficace le taux de glycémie.
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WO2005042011A1 (fr) * 2003-11-04 2005-05-12 Novo Nordisk A/S Composition pharmaceutique contenant un polypeptide de proteine c et un regulateur de glucose sanguin
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US10117909B2 (en) 2008-10-17 2018-11-06 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1 agonist
US10028910B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1-agonist and methionine
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EP3417871A1 (fr) * 2009-11-13 2018-12-26 Sanofi-Aventis Deutschland GmbH Composition pharmaceutique comprenant un agoniste glp-1, de l'insuline et de la methionine
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
EP3831402A1 (fr) * 2009-11-13 2021-06-09 Sanofi-Aventis Deutschland GmbH Composition pharmaceutique comprenant un agoniste du glp-1, une insuline et de la méthionine
WO2011058083A1 (fr) * 2009-11-13 2011-05-19 Sanofi-Aventis Deutschland Gmbh Composition pharmaceutique comprenant un agoniste de glp-1, une insuline et de la méthionine
EP2554183A1 (fr) * 2009-11-13 2013-02-06 Sanofi-Aventis Deutschland GmbH Composition pharmaceutique comprenant un agoniste GLP-1, de l'insuline et de la méthionine
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