Composition for treating heart failure

Abstract

To provide drugs and methods for preventing, treating or delaying human heart failure.SOLUTION: A method for treating chronic heart failure patient using an agent comprising neuregulin is provided. The method comprises conducting a companion diagnostic test of each patient prior to the treatment, and according to the test result of the companion diagnostic test, a treatment suitable for the patient is provided. When the test result is within a preferred treatment zone, the patient is suitable for the heart failure treatment by administering an effective amount of neuregulin.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] [1. Technical Field] The present invention relates to a method for preparing a medicament for preventing, treating, or delaying heart failure in humans. Use of cycloregulin protein and the prevention, treatment, or administration of said agent to human heart failure In particular, the present invention relates to a method for the prevention or delay of neuregulin-mediated inflammatory responses. Drug-assisted prevention, treatment, or delay of heart failure in specific populations of patients with chronic heart failure This provides a method for:

[0002] [2. Background technology] Approximately 5 million Americans suffer from heart failure, with more than 550,000 new cases each year have been diagnosed with symptoms of heart failure. Current drug treatments for heart failure involve dilating blood vessels and Angiotensin-converting enzyme (ACE), a vasodilator that lowers blood pressure and reduces the workload of the heart Although the mortality rate has decreased significantly, the use of ACE inhibitors has The actual mortality reduction with the use of steroids is only 3-4% on average, and there are no potential side effects. There are additional limitations associated with other options for preventing or treating heart failure. For example, heart transplants are significantly more expensive and invasive than drug treatments, and require the use of donor hearts. The use of mechanical devices such as biventricular pacemakers is also limited. Therefore, new treatments that take into account the shortcomings of current treatments are needed. There is a need.

[0003] One promising new treatment is for people with or at risk of developing heart failure. Neuregulin (hereinafter referred to as "NRG") is administered to patients with N RGs are a family of EGF-like growth factors, consisting of NRG1, NRG2, NRG3, and NR A family of structurally related growth factors that includes G4 and their isoforms It contains a family of differentiation factors that mediate breast cancer cell differentiation and milk protein secretion. Stimulation of neural crest cells, differentiation induction of Schwann cells, acetylcholine receptors in skeletal muscle cells involved in a range of biological responses, such as stimulating synthesis and promoting cardiac cell survival and DNA synthesis. There are severe defects in ventricular trabecular formation and dorsal root ganglion development, and the neuregulin gene In vivo studies of gene-targeted homozygous mouse embryos have shown that neuregulins regulate the heart and nervous system. It has been shown to be essential for the development of the sect.

[0004] NRGs bind to the EGF receptor family, which is made up of EGFR , ErbB2, ErbB3, and ErbB4, which are involved in cell proliferation, cell They play important roles in multiple cellular functions, such as differentiation and cell survival. , a protein tyrosine kinase receptor with an extracellular ligand-binding domain, a transmembrane kinase It consists of a tyrosine kinase domain and a cytoplasmic tyrosine kinase domain. ErbB3 or Erb After NRG binds to the extracellular domain of B4, it induces a conformational change, which leads to the formation of ErbB3 and ErbB4. Heterodimer formation occurs between ErbB4 and ErbB2, or ErbB4 itself This results in the formation of a homodimer of the receptor, which binds the C-terminal domain of the receptor to the inner surface of the cell membrane. The phosphorylated intracellular domain is then transported into the cell. In this case, it binds to additional signaling proteins and activates the corresponding downstream AKT or ERK signaling. This activates the cytosolic pathway, triggering a series of cellular responses, such as: Stimulation or reduction of cell proliferation, cell differentiation, cell apoptosis, cell migration, or cell adhesion Among these receptors, ErbB2 and ErbB4 are mainly involved in the heart. is being expressed.

[0005] The EGF-like domain of NRG-1 (50 to 64 amino acids in size) Previous studies have shown that this is sufficient to bind to and activate the receptors of Neuregulin-1β (NRG-1β) binds to ErbB3 and ErbB4 with high affinity. It has been shown that the orphan receptor ErbB2 can directly bind to ErbB3. It binds ErbB3 and ErbB4 with higher affinity than the homodimers of ErbB3 and ErbB4. It can form heterodimers with ErbB4. Studies in neural development have shown that it is important for the formation of the sympathetic nervous system. The formation of ERGF requires the intact NRG-1β, ErbB2, and ErbB3 signaling pathways. Targeted disruption of NRG-1β or ErbB2 or ErbB4 has been shown to improve cardiac function. Defective cardiac development results in embryonic lethality. Recent studies have shown that it maintains normal cardiac function in adults. In addition, the roles of NRG-1β, ErbB2, and ErbB4 in cardiovascular development are also unclear. NRG-1β has been shown to enhance sarcomere organization in adult cardiac muscle. Recombinant NRG has been shown to be effective in clinical trials and in different animal models of heart failure. Administration of the EGF-like domain of β-1β significantly improved or prevented the deterioration of myocardial function. These results support the use of NRG-1 as a key compound for the treatment of heart failure. However, there is little evidence that treatment with NRG-1 could provide long-term benefits to patients with heart failure. Whether these benefits are available to all patients with chronic heart failure or to a subset of patients More evidence is still needed as to whether the

[0006] 3. Summary of the Invention In a human clinical trial of neuregulin for the treatment of heart failure, applicant Assessment by New York Heart Association (NYHA) cardiac function classification or patient NT-proBNP Alternatively, measuring plasma levels of BNP may reveal significant therapeutic benefit from neuregulin. We found that it is possible to select patients with heart failure who are likely to receive treatment. This includes a wide decline.

[0007] Applicant believes that NRGs are involved in cardiomyocyte differentiation, sarcomere and cytoskeletal organization, and cellular function. Applicant has demonstrated that the compound enhances cell adhesion in clinical trials and in different clinical settings of heart failure. In animal models, NRG significantly improved or prevented the deterioration of myocardial function. We also found that neuregulin, neuregulin polypeptide, and neuregulin significantly protect against Neuregulin derivatives, or compounds that mimic the activity of neuregulin, are within the scope of the present invention. Included in.

[0008] That is, in a first aspect of the present invention, a pharmaceutical composition containing an effective amount of neuregulin is administered to treat chronic cardiac The pharmaceutical composition was administered to treat patients with rheumatoid arthritis, and the patients obtained significant benefits from the pharmaceutical composition. In some embodiments, the benefit is a significant reduction in mortality. and a significant reduction in rehospitalization. In one embodiment, the benefit indicates improvement in chronic heart failure. In one embodiment, the pharmaceutical composition is an induction regimen. In an optimized embodiment, the induction regimen comprises administering to the patient the pharmaceutical composition The method includes administering the compound for at least 3, 5, 7, or 10 consecutive days. In embodiments, the pharmaceutical composition is administered at least 3, 6, or 12 days after the induction regimen. It is administered to the patient in a maintenance regimen for a period of one month. In an optimized embodiment, the regimen comprises administering the pharmaceutical composition every 3, 5, 7, or 10 days. This includes administering the drug every 24 hours.

[0009] In a second aspect, the present invention provides a method for improving survival or reducing mortality in patients with chronic heart failure. and administering a pharmaceutical composition containing an effective amount of neuregulin to the patient with chronic heart failure. In one embodiment, the pharmaceutical composition is administered to the patient in an induction regimen. In an optimized embodiment, the induction regimen comprises administering the pharmaceutical composition to at least one patient. In some optimized embodiments, the administration of the compound is for at least 3, 5, 7, or 10 consecutive days. wherein the pharmaceutical composition is administered for at least 3, 6, or 12 months after the induction regimen; In an optimized embodiment, the patient is administered a regimen of The method includes administering the pharmaceutical composition every 3, 5, 7, or 10 days.

[0010] In a third aspect of the present invention, a therapeutically effective amount of neuregulin is administered to reduce the blood levels of NT-proBNP. Treating patients with chronic heart failure whose plasma levels are within the preferred therapeutic range before treatment with neuregulin In one embodiment, the preferred therapeutic range is 4000 fmol / In another embodiment, the preferred therapeutic range is 1600 fmol / ml to In yet another embodiment, the preferred therapeutic range is between 1 and 4000 fmol / ml. In another preferred embodiment, the plasma level is measured by immunoassay. It is measured by standard methods.

[0011] In a fourth aspect of the present invention, a therapeutically effective amount of neuregulin is administered to a subject in need of cardiac support in accordance with the NYHA functional classification. It is therefore used to treat patients with chronic heart failure who are classified into specific cardiac functional classes. In one embodiment, the specific cardiac function class is NYHA class II. In this state, the particular cardiac function class is NYHA class III.

[0012] In a fifth aspect, the present invention provides a method for selecting a heart failure patient for treatment with neuregulin. This method involves measuring the plasma levels of NT-proBNP in the above patients. In one embodiment, a level of 4000 fmol / ml or less is In another embodiment, the patient is suitable for treatment of heart failure with 160 Levels between 0 fmol / ml and 4000 fmol / ml indicate neuregulin-induced cardiac failure. In yet another embodiment, the 1600 mol A level of neuregulin below 1 / ml indicates that the patient is suitable for heart failure treatment. are.

[0013] In a sixth aspect, the present invention provides a method for selecting a heart failure patient for treatment with neuregulin. This method evaluates cardiac function class according to the NYHA cardiac function classification. In one embodiment, NYHA class II is a neuregulin-induced cardiac failure. In another embodiment, the patient is in NYHA class III. These findings indicate that these patients are suitable candidates for neuregulin therapy for heart failure.

[0014] In a seventh aspect, the present invention provides a method for selecting heart failure patients for treatment with neuregulin. In one embodiment, the diagnostic kit is for detecting N in a patient with heart failure. Contains immunoassay reagents for measuring plasma levels of T-proBNP, 4000 fmol / ml or less indicates that patients are suitable for neuregulin therapy for heart failure. In another embodiment, the level is between 1600 fmol / ml and 4000 fmol / ml. This indicates that these patients are suitable candidates for neuregulin therapy for heart failure. In this embodiment, a level of 1600 mol / ml or less indicates neuregulin treatment of heart failure. This indicates that the patient is suitable for treatment.

[0015] In an eighth aspect of the present invention, there is provided a use of a neuregulin protein for preparing a medicament. These drugs can be administered to patients with chronic heart failure for long-term benefit. In one embodiment, the long-term benefit is improved survival. The long-term benefit is a reduction in hospital readmissions. In another embodiment, the long-term benefit is a reduction in In one embodiment, the drug is an improvement in a biomarker that indicates long-term prognosis of chronic heart failure. The agent is administered to the patient in an induction regimen. The regimen involves administering the drug for at least 3, 5, 7, or 10 consecutive days. In an optimized embodiment, the agent is administered at least 3, 6, or 1 day after the induction regimen. In one optimized embodiment, the patient is administered a controlled regimen for two months. The management regimen involves administering the above medications every 3, 5, 7, or 10 days. .

[0016] In a ninth aspect of the present invention, there is provided a method for treating chronic heart failure with a neuregulin protein. A companion diagnostic test was provided: N-terminal pro-brain natriuretic peptide (NT- proBNP) is used as a biomarker for the companion diagnostic test. In some embodiments, levels of 4000 fmol / ml or less indicate neuregulin-induced heart failure. In another embodiment, 1600 fmol / ml Levels between 4000 and 4000 fmol / ml are considered appropriate for patients with heart failure treated with neuregulin. In yet another embodiment, the level of 1600 mol / ml or less is These findings suggest that these patients are suitable candidates for neuregulin therapy for heart failure.

[0017] In a tenth aspect of the present invention, there is provided a method for treating chronic heart failure using neuregulin. The method includes a pre-treatment evaluation procedure, and according to the results of the evaluation, each patient is In one embodiment, the evaluation determines whether a person is suitable for receiving regulin therapy. The procedure includes determining the NYHA functional classification of the patient with chronic heart failure. The evaluation procedure included testing plasma NT-proBNP or plasma BNP in each patient with chronic heart failure. I am doing this.

[0018] In an eleventh aspect of the present invention, a patient with chronic heart failure is selected from those suitable for neuregulin protein treatment. A companion diagnostic kit for determining whether a patient has the above-mentioned companion diagnostic kit is provided. Diagnostic kits include plasma NT-proBNP or plasma BNP test kits, and the above kits. Patients are eligible for neuregulin protein therapy according to the instructions and test results. It includes instructions on how to determine if

[0019] 4. Detailed Description of the Invention For clarity of disclosure, and not by way of limitation, the following detailed description of the invention is provided below. All publications mentioned in this specification are incorporated by reference in their entirety. by reference to disclose and describe the methods and / or materials involved in the incorporated herein.

[0020] A.Definition Unless otherwise defined, all technical and scientific terms used herein Terms have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications, and other patents mentioned herein are hereby incorporated by reference. The publications described in this section are incorporated herein by reference in their entirety. Definitions are included in the patents, applications, published applications, and In cases where there is a contradiction or inconsistency with definitions set forth in other publications, The definitions set forth take precedence over definitions incorporated herein by reference.

[0021] As used herein, the singular forms "a," "an," and "the" refer to Unless the context clearly dictates otherwise, use "at least one" or "one or more" It means "number."

[0022] As used herein, "neuregulin" as used in the present invention or "NRG" means a molecule that binds to ErbB2, ErbB3, ErbB4, or a combination thereof. represents a protein or peptide that can activate all neuregulin isoforms. Form, neuregulin EGF-like domain alone, neuregulin EGF-like domain included Polypeptides, neuregulin variants or derivatives, and the receptors described above that are similarly active The term "neuregulin-like gene product" includes any type of neuregulin-like gene product that activates the neuregulin-like protein (details below), but is not limited to this. Neuregulins also include, but are not limited to, NRG-1, NRG-2, NRG Mimicking the activities of NRG-3 and NRG-4 proteins, peptides, fragments, and neuregulins The neuregulins used in the present invention include compounds that bind to the ErbB receptors described above. It can activate receptors and regulate their biological responses. For example, in skeletal muscle cells, stimulates the synthesis of acetylcholine receptors in cardiac cells and / or promotes cardiac cell differentiation, survival and Increases DNA synthesis. Neuregulins also substantially alter their biological activity. Also included are variants with conservative amino acid substitutions that do not alter the amino acid sequence. Conservative substitutions are known to those of skill in the art and are intended to enhance the biological activity of the resulting molecule. Those skilled in the art will generally be able to make modifications without altering the essential amino acid sequences of a polypeptide. It was found that single amino acid substitutions in the target region did not substantially alter biological activity. (e.g., Watson et al. Molecular Biology of the Gene, 4th Edition, 1987, (See The Bejacmin / Cummings Pub. Co., p. 224.) In a preferred embodiment, the present invention The neuregulin used in this study is ErbB2 / ErbB4 or ErbB2 / ErbB4. The peptide binds to and activates bB3 heterodimers. Column:SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPN NRG-1β2, including EFTGDRCQNYVASFYKAEELYQ (SEQ ID NO: 1) The peptides containing residues 177-237 of the isoform are included, but are not limited to these. The above peptide containing residues 177-237 of the NRG-1β2 isoform The EGF-like peptides shown to be sufficient to bind to and activate the receptors Includes the domain.

[0023] As used herein, "epidermal growth factor-like domain" or "EGF-like domain" refers to a "ErbB2" binds to ErbB2, ErbB3, ErbB4, or a combination thereof and activates them. and has structural similarity to the EGF receptor binding domain disclosed in the following document: The polypeptide motifs encoded by the neuregulin gene are WO 00 / 64400, Holmes et al., Science, 256:1205-1210 (1992); US Patent Nos. 5,530,109 and 5,716,930; Hijazi et al., Int. J. Oncol., 13:1061-1067 (1998) ; Chang et al., Nature, 387:509-512(1997); Carraway et al., Nature, 387:512-516 (1997); Higashiyama et al., J. Biochem., 122:675-680 (1997); and WO 97 / 09425. The contents of these documents are incorporated herein by reference in their entirety. The EGF-like domain is a heterodimer of ErbB2 / ErbB4 or ErbB2 / ErbB3. In one embodiment, the EGF-like domain binds to and activates the ribodimers. In one embodiment, the amino acid sequence of the receptor binding domain of NRG-1 is included. The EGF-like domain is located at 177-226, 177-237, or 177- In one embodiment, the E The GF-like domain contains the amino acid sequence of the receptor-binding domain of NRG-2. In an embodiment, the EGF-like domain has the amino acid sequence of the receptor binding domain of NRG-3. In one embodiment, the EGF-like domain comprises a receptor-binding domain of NRG-4. In one embodiment, the EGF-like domain comprises the amino acid sequence of a rice As described in US Patent No. 5,834,229, Ala Glu Lys Glu L ys Thr Phe Cys Val Asn Gly Gly Glu Cys Phe Me It contains the amino acid sequence t Val Lys Asp Leu Ser Asn Pro.

[0024] The neuregulin protein is preferably in the form of a pharmaceutical composition, and the composition, The dosage and route of administration can be determined according to methods known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro (E Mack Publishing Company, April 1997; Therapeutic Peptides and Proteins: F ormulation, Processing, and Delivery Systems, Banga, 1999; and Pharmaceutical Fo rmulation Development of Peptides and Proteins, Hovgaard and Frkjr (Ed.), Taylor & Francis, Inc., 2000; Medical Applications of Liposomes, Lasic and Papahadjopou los (Ed.), Elsevier Science, 1998; Textbook of Gene Therapy, Jain, Hogrefe & Hub er Publishers, 1998; Adenoviruses: Basic Biology to Gene Therapy, Vol. 15, Seth , Landes Bioscience, 1999; Biopharmaceutical Drug Design and Development, Wu-Pon g and Rojanasakul (Ed.), Humana Press, 1999; Therapeutic Angiogenesis: From Basi c Science to the Clinic, Vol. 28, Dole et al. (Ed.), Springer-Verlag New York, 1 See 999).

[0025] The neuregulin protein can be administered orally, rectally, topically, by inhalation, or by buccal administration. administration (sublingual administration, etc.), parenteral administration (subcutaneous administration, intramuscular administration, intradermal administration, or intravenous administration, etc.) ), transdermal, or other suitable routes of administration. The most appropriate route in a case will depend on the nature and severity of the condition being treated and the specific The properties of the neuregulin protein are determined by the above. Alternatively, the neuregulin protein can be administered in a pharmaceutically acceptable carrier. Preferably, the compound is administered in combination with a carrier or excipient. In this manner, any suitable pharmaceutically acceptable carrier or excipient may be used. Any suitable carrier or additive may be used (see Remington: The Science and Practice ice of Pharmacy, Alfonso R. Gennaro (Editor) Mack Publishing Company, April 1997 etc.).

[0026] According to the present invention, the neuregulin protein may be administered alone or in combination with other agents, carriers, or With additives, it can be administered by intracavernous injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, or oral administration. The formulation may be adapted for any suitable route of administration, such as oral or topical administration. A formulation for injection in unit dosage form in an ampoule or multi-dose container containing The formulation may be in the form of a suspension, solution, emulsion, or the like in an oily or aqueous vehicle. The formulation may contain formulation agents such as suspending agents, stabilizing agents, and / or dispersing agents. Before use, the active ingredient should be mixed with a suitable vehicle, sterile pyrogen-free water, or other suitable It may be in powder form to be made into a solution. Topical administration in the present invention may be in the form of foam, gel, cream, Ointments, skin patches, or pastes may be used.

[0027] Pharmaceutically acceptable compositions that can be used in the present invention, and methods of administering them, are disclosed in U.S. Pat. ,736,154;6,197,801B1;5,741,511;5,886,039 ; 5,941,868; 6,258,374B1; and 5,686,102 This includes, but is not limited to, those

[0028] The therapeutic or prophylactic dosage will vary depending on the severity of the condition to be treated and the route of administration. The dose, and possibly the frequency of administration, will vary depending on the age, weight, condition, and response of the individual patient. It changes to:

[0029] Your doctor will advise you on when and how to stop or discontinue treatment due to toxic or adverse effects. Know whether to discontinue treatment or adjust treatment to a lower dose. Conversely, the attending physician may decide to discontinue treatment at any time if the clinical response is not adequate (excluding toxic side effects). We also recognize that treatment may need to be adjusted to a higher dose.

[0030] Any suitable route of administration may be used. Dosage forms include tablets, lozenges, and the like. Includes tablets, wafers, dispersions, suspensions, solutions, capsules, salves, etc. Remington's Pharmacy In practical use, according to conventional drug synthesis techniques, The neuregulins, alone or in combination with other drugs, can be used as active ingredients in a combination drug. β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, etc. The carrier may be combined with a pharmaceutical carrier or excipient such as the above. For parenteral administration such as intravenous injection or infusion, In preparing the composition, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc. Similar pharmaceutical vehicles known to those skilled in the art may also be used. , 5% w / v dextrose, normal saline, or other solutions These include, but are not limited to, the following: The total dose of the neuregulin protein is administered in an amount ranging from about 1 to 2000 ml of intravenous fluid. The amount of diluent will vary depending on the total dose.

[0031] The present invention also provides kits for carrying out the therapeutic regimens of the present invention. is administered in a pharmaceutically acceptable form in a therapeutically effective amount alone or in combination with other drugs. The preferred dosage form is a non-steroidal anti-inflammatory drug (NSAID) containing one or more containers of the neuregulin protein. Sterile saline, dextrose solution, buffer, or other pharmaceutically acceptable sterile fluids The composition may be lyophilized or dried. In this case, the kit is sterile to reconstitute the compound to make an injectable solution. The container may further contain a pharmaceutically acceptable solution, which is preferably a pharmaceutically acceptable solution. Examples of suitable solutions include saline and dextrose solution.

[0032] In another embodiment, the kit of the present invention is packaged in a sterile form for injection of the composition. needles or syringes, preferably wrapped, and / or wrapped alcohol pads It further comprises instructions for administering the composition by a physician or a patient. Good too.

[0033] As used herein, "treat," "treatment," and "treating" refer to the treatment of a disease. any method of ameliorating or otherwise altering for the better the symptoms of an illness or disease The effectiveness of a treatment can be measured in terms of completely or partially preventing a disease or its symptoms. and / or for the prevention of diseases and / or harmful effects resulting from said diseases. Treatment may be therapeutic in terms of partial or complete healing. Treatment may involve the administration of any of the compositions herein. The pharmaceutical uses of

[0034] As used herein, "heart failure" refers to the inability of the heart to produce blood at the rate required by metabolic tissues. Heart failure refers to an abnormality in the function of the heart that prevents it from pumping blood. A wide range of conditions including tachycardia, familial hypertrophic cardiomyopathy, ischemic heart disease, idiopathic dilated cardiomyopathy, and myocarditis Heart failure includes, but is not limited to, ischemic, congenital, rheumatoid arthritis, and other heart disease conditions. It can arise from many causes, including inflammatory, viral, toxic, or idiopathic forms. Cardiac atherosclerosis is a serious disease state that is a precursor to congestive heart failure and cardiac arrest.

[0035] As used herein, "protein" refers to any protein, unless the context clearly dictates otherwise. Unless otherwise specified, the term "polypeptide" is synonymous with "polypeptide" or "peptide."

[0036] As used herein, "plasma" refers to plasma unless the context clearly dictates otherwise. It is synonymous with "serum."

[0037] As used herein, "long-term benefit" refers to the long-term benefit of a treatment or intervention following that treatment or intervention. This represents a benefit that cannot be seen in the short term due to intervention. Long-term benefit is defined as improved survival, reduced rehospitalization, or biomarkers that demonstrate long-term outcomes. In one embodiment, the time period for observing the benefit is about 6 months. In one embodiment, the period of time for observing the benefit is about 1 year. The period of time during which the benefit is observed is about 2 years. In other embodiments, the period of time during which the benefit is observed is about 2 years. is about 3, 5, 10 or more years.

[0038] As used herein, "survival" refers to the duration or probability that a patient is alive. The duration of a disease can be measured and expressed as survival time or survival rate. Survival time is the time from diagnosis or treatment to death. Survival rates are the percentage of people who are alive for a given period after diagnosis or treatment. For each patient, any increase in survival time due to a treatment or intervention is considered a benefit. For a patient population or large population, the average survival time or Increased survival can be considered a benefit.

[0039] As used herein, "readmission" refers to the number of times a patient is admitted to a hospital within a certain period of time. Hospital admissions can be for any illness, but It may be due only to the same disease as the one being treated. A reduction in the number of readmissions can be considered a benefit for a patient population or a large population. ,A reduction in the total or average number of readmissions can be considered a benefit.

[0040] As used herein, "N-terminal brain natriuretic peptide" or "NT-p "roBNP" refers to the inactive N-terminal proBNP, the latter of which is primarily found in the myocardium of the left heart wall. It is a prohormone of BNP, a hormonally active natriuretic peptide released from cells. In response to the stretching and tension of the myocardial wall, the prohormone proBNP is proteolyzed. Upon cleavage, it is separated into BNP and the inactive hormone residue NT-proBNP.

[0041] BNP and NT-proBNP plasma levels are important in patients with suspected or confirmed heart failure. These are promising items for the daily management of patients with BNP and NT-proB in clinical settings. Many studies on the use of NP have addressed its diagnostic properties, and the relationship between BNP and NP has been unclear. Increasing evidence is available to support the prognostic value of T-proBNP. NT-proBNP has a half-life in the blood that is approximately six times longer than BNP, making it a useful diagnostic tool for heart failure. Plasma NT-proBNP levels are more widely used as a diagnostic or prognostic marker. For example, commercial kits from Roche or Biomedica are available. Examples of commercially available kits include, but are not limited to, those available from the company NT- ProBNP levels were detected by a kit from Biomedica (Austria). It was.

[0042] Blood levels of BNP and NT-proBNP were both markers in patients with poor prognosis. Since the values ​​of β-glucan are generally high, it is used for screening and diagnosing heart failure, and In the present invention, BNP or NT-proBNP is useful for determining the prognosis of heart failure. found that plasma levels of neuregulin indicate patients suitable for heart failure treatment. Indeed, any diagnostic or prognostic marker of heart failure may be indicative of whether a patient is receiving neuregulin therapy for heart failure. The NT-p identified in the present invention can be used to determine whether a patient is suitable for treatment. roBNP plasma levels indicate heart failure patients who would derive significant therapeutic benefit from neuregulin They should be used as guidelines rather than limitations for selecting a Using plasma levels of 5000 fmol / ml, the therapeutic benefit of neuregulins was observed. It is still possible to select patients with heart failure who are likely to be affected, but some of these patients may be more susceptible to Some patients may derive less benefit from treatment.

[0043] As used herein, the "New York Heart Association" or "NYHA" cardiac function Classification is a simple way of classifying the degree of heart failure. This classification determines the degree of limitation ( Restrictions / symptoms relate to varying degrees of normal breathing and shortness of breath and / or severe pain Patients were classified into four categories based on the degree to which they experience symptoms during normal physical activity (I, symptoms during normal physical activity) and no limitations (e.g., shortness of breath when walking or climbing stairs); II, mild symptoms ( mild shortness of breath and / or pain) and mild limitation during usual activities; III, usual Symptoms prevent you from engaging in activities that are less than normal (e.g., walking short distances (20-100 m)) The patient is severely restricted and symptoms are only stable at rest. IV, many patients are bedridden, and at rest Symptoms also appear in the elderly, causing significant limitations.

[0044] As used herein, an "activity unit," "EU," or "U" refers to the maximum reaction This means the amount of standard that can induce 50% of the active unit for a given active substance. To determine the EC50, the EC50 should be measured. If the EC50 of the serotonin was 0.1 μg, this would be 1 unit. If 1 μg of the product is used, 10EU (1 / 0.1) is used. can be determined by any method known in the art and has been used by the inventors This determination of the active unit is carried out in the genetically engineered product and This is important for the quality control of drugs used in clinical practice. Therefore, different formulations and / or products from different batch numbers may be manufactured to the same standard. It can be quantified by

[0045] The following shows the binding of NRG to cell surface ErbB3 / ErbB4 molecules and ErbB2 linker. An exemplary, rapid method for determining the biological activity of NRG-1 via indirect mediation of phosphorylation. , a sensitive, flexible, and quantitative method (Michael D. Sadick et al., 1996, Analytical Biochemistry, 235:207-214 and WO03 / 099300, etc.).

[0046] Briefly, it is called Kinase Receptor Activity Enzyme-Linked Immunosorbent Assay (KIRA-ELISA). The assay involves two separate microtiter plates, one of which contains Titer plates are for cell culture, ligand stimulation, and cell lysis / receptor solubilization The other microtiter plate was used for receptor capture and phosphotyrosine ELISA. The assay was performed to measure NRG-induced IL-1 expression in the adherent breast cancer cell line MCF-7. The analysis of ErbB2 activity was carried out using intact receptor stimulation. Proteins were solubilized via Triton X-100 lysis, and receptors were identified as ErbB3 or ELISA coated with ErbB2-specific antibody that does not cross-react with ErbB4 The degree of receptor phosphorylation was determined by anti-phosphotyrosine ELISA. A reproducible standard curve was established for heregulin β1(177-244). Created with an EC50 of approximately 360 pM. Ideal HRGβ1(177-244) sample KIRA-ELISA and quantitative anti-phosphotyrosine Western blot analysis When the analysis is performed by the The above-described assay method is based on the E activity due to the interaction of HRG with ErbB3 and / or ErbB4. Tyrosine phosphorylation of rbB2 can be clearly quantified.

[0047] Since most genetically engineered drugs are proteins and polypeptides, their activity is Evaluate based on the amino acid sequence or the active center formed by its steric structure. The activity titer of proteins and polypeptides does not correspond to their absolute amount, The activity can be evaluated in weight units, like the weight units of chemicals. However, the biological activity of genetically engineered drugs is generally consistent with their pharmacodynamic properties. Furthermore, the potency determination system established through a predetermined biological activity determines the potency unit. Therefore, the evaluation of biological activity can be carried out by determining the potency of a substance having biological activity. It can be part of the measurement process and is an important element of the quality control of genetically engineered medicines. For the quality control of manufactured products and clinically used drugs, biological activity criteria are used. Making a decision is important.

[0048] The amount of standard that can induce 50% of the maximum response is defined as an activity unit (1 EU). Therefore, different preparations and products from different batch numbers are not held to the same standards. It can be quantified by

[0049] B. Working Example Example 1: Survival of rats with CHF following different routes of Neucardin™ administration Effect on survival rate introduction In this study, we used a coronary artery ligation (CAL)-induced CHF model to investigate the effects of microinjection. Neucar by IV infusion using an injection pump or subcutaneous (SC) bolus The effect of din™ administration on survival and cardiac hemodynamics was assessed by comparing CAL and The study was conducted 120 days after Neucardin administration, which began 4 weeks after the start of the study. Echocardiography and cardiac remodeling to confirm function and recovery from CAL I also used it.

[0050] 2. Method 2.1. Test animals: Strain, origin: Wistar rats, Shanghai SLAC Laboratory Animal CO. LTD; Weight 200±10g, male; 2.2 Test Subjects 2.2.1 Neucardin(TM) ID: Injectable recombinant human neuregulin-1 (rhNRG-1, Neucardin trademark)) Lot number: 200607009 Manufacturer:Zensun (Shanghai) Sci & Tech Co., Ltd Dosage form: Lyophilized powder Appearance: White or off-white cake Labeled rhNRG-1 dosage: 250 μg / vial Specific activity: 4897U / vial Storage conditions: 2~8℃ 2.2.2 Excipients: ID: placebo of recombinant human neuregulin-1 Dosage form: Lyophilized powder Appearance: White or off-white cake Composition: Human serum albumin, mannitol, phosphate, sodium chloride Storage conditions: 2~8℃ 2.3 Steps: 2.3.1 Method for creating a rat CHF model The LAD of rats was ligated. Briefly, ketamine hydrochloride (100 mg / kg, I Rats were anesthetized with PBS (P), and the chest was shaved and sterilized. The rats were intubated and kept in room air. Mechanical oxygen was supplied (respiratory rate: 60 breaths / min, tidal volume: 20 ml). A left thoracotomy was performed between the fourth and fifth intercostal spaces, and the skin was incised along the left sternal line. The 4th rib was resected toward the sternum. The pericardial sac was punctured to expose the heart. Silk suture The LAD was ligated approximately 2 mm from the origin using a 6-0 catheter. The rat was then decompressed and the chest was closed in three layers (ribs, muscle, and skin). Once the animals were free from anesthesia, they were returned to their cages. If the EF value is 30-45%, a formal test is recommended. All groups of rats were housed in five cages and had free access to standard chow. The room temperature was kept at 21±1°C, and the light / dark cycle was 12 hours. Switched the dark.

[0051] 2.3.2 IV infusion with a microinjection pump IV infusion of vehicle or Neucardin™ was administered via the tail vein. To perform the procedure, an appropriate rat restrainer corresponding to the rat's weight was used. The rat was placed near the restrainer and gently placed in the apparatus. Usually, the rat entered the restrainer without assistance. Afterwards, the tail was moistened with alcohol to increase blood flow in the veins and soften the stratum corneum of the skin. The rat's tail was wiped with a damp gauze. Two tail veins on the lateral side were identified and inserted into the belly of the needle. Insert the needle into the tail vein 2-3 cm from the end of the tail, with the needle pointing upward so that it is roughly parallel to the vein. The needle was inserted 2 mm into the tail vein. The needle was fixed to the tail with medical tape. 2-0.4 ml / hour) and medication via microinjection pump or bolus injection or vehicle infusion was initiated.

[0052] 2.3.3 SC bolus An SC bolus of vehicle or Neucardin™ was administered into the rat's back. To perform this procedure, an appropriate rat restrainer was used, corresponding to the weight of the rat. The rat's back was wiped with alcohol-soaked gauze to disinfect the skin. Insert the needle subcutaneously into the rat's back 3-4 cm, with the needle pointing upward and parallel to the skin. The needle was fixed to the back with medical tape and connected to the irrigation tube. After that, the rat was placed near the restrainer and gently placed in the device. After closing the restrainer, the bolus injection was started.

[0053] 2.3.4 Experimental groups and drug infusions The MI rats were randomly divided into the following four groups according to their EF values:

[0054] Group A (control experiment with IV and SC bolus): n = 58 rats, microinjected IV infusion of vehicle by injection pump, 0.2 ml, 8 hours daily for the first 10 days / hr speed, and a SC bolus of excipient (same amount as Neucardin™) The treatment was administered every 5 days until the 120th day.

[0055] Group B (Neucardin™ SC bolus): n=58, microinfusion IV infusion of the vehicle by injection pump for 8 hours daily for the first 10 days at a rate of 0.2 m 1 / hr and a SC bolus of Neucardin™ (10 μg / day) was administered every 5 days until the 120th day.

[0056] Group C (Neucardin™ IV infusion): n=57, microinjected Neucardin™ IV infusion (0.625 μg / kg / day) via injection pump The injections were performed daily for 8 hours for the first 10 days at a rate of 0.2 ml / hour, and the excipient was administered SC. A bolus (same amount as Neucardin™) was administered every 5 days until 120 days.

[0057] Group D (Neucardin™ IV infusion and SC bolus): n=57 , IV infusion of Neucardin™ via microinjection pump (0. 625 μg / kg / hour) at a rate of 0.2 ml / hour for 8 hours daily for the first 10 days and administering a SC bolus of vehicle (same amount as Neucardin™) on days 1, 6, and 7. Neucardin™ administered on day 11, then every 5 days from day 16 through the final day was administered as a SC bolus (10 μg / day).

[0058] 2.3.5 Acquired Data Survival rate; echocardiography parameters; hemodynamic parameters; 3. Results 3.1 Survival rate Table 1 shows the survival rates among the groups. The survival rates were as follows: Group A (IV point of vehicle) drops and SC bolus), 48.3%, and Group B (Neucardin™ S 62.1% in Group C (IV infusion of Neucardin™) and 62.1% in Group C (IV infusion of Neucardin™). Group D (IV infusion and SC bolus of Neucardin™) was 64.9%. ) was 82.5%. The survival rate or mean survival time of rats that died in groups B, C, and D showed improvement or duration longer than Group A, with Group D showing the greatest effect.

[0059] [Table 1]

[0060] 3.2 Echocardiography parameters Echocardiography parameters are shown in Table 2. Four weeks after coronary artery ligation and at the end of the study Before administration of the substances, the CHF rats were randomly divided into four groups based on the EF values. As shown in the figure, there were no significant differences between the four groups before treatment (BT). After that, EF values ​​were 30.7 ± 3.1 in the vehicle group and 30.7 ± 3.1 in the SC bolus group, respectively. In the Neucardin™ group, 32.9 ± 4.1; in the IV infusion of Neucardin 33.5±3.4 in the rdin™ group, and 33.5±3.4 in the IV infusion and SC bolus groups. In the Neucardin™ group, it was 36.2 ± 4.8. The EF and FS values ​​of groups B, C, and D were higher than those of group A. It was.

[0061] [Table 2]

[0062] 3.3 Hemodynamic parameters Table 3 shows the MAP, HR, ±dp / dt of the four groups of anesthetized animals on day 121. , LVEDP, and LVSP measurements are shown. C Administered either by bolus or IV infusion (Groups B and C ), Neucardin™ showed a dp / dt of 19. 0.6% and 27.1%, and -dp / dt 22.5% and 29.8%, respectively, significantly Neucardin™ was administered by both IV infusion and SC bolus. In the group D, mean arterial pressure (MAP, 1 12.3±5.5mmHg), left ventricular systolic pressure (LVSP, 139.4±9.8mmHg ), +dp / dt(7012.1±903.0mmHg / sec), -dp / dt(-435 MAP (3.2±847.6mmHg / sec) was significantly increased. These values ​​of LVSP, +dp / dt, and -dp / dt were obtained from rats receiving vehicle. were 10.6%, 9.2%, 38.5%, and 37.5% higher than those of the control group, respectively. These results showed that groups B, C, and D were significantly superior to group A in terms of hemodynamic parameters. The results showed that the effect was better than that of group D, with group D showing the highest effect.

[0063] [Table 3]

[0064] [Table 4]

[0065] 4. Conclusion For combined administration of Neucardin™ by IV infusion and SC bolus Whether the peptide was administered by only one route or by only one other route, the subjects were treated with the vehicle. The survival rate of rats in which CHF was induced by CAL was higher than that of rats in which CHF was induced by CAL. and cardiac function parameters improved.

[0066] Example 2: Recombinant Human Neuregulin 1 in Patients with Chronic Heart Failure Based on Standard of Care A randomized, double-blind, multicenter, placebo-controlled trial to evaluate efficacy and safety To evaluate the effect of recombinant human neuregulin-1 infusion on chronic heart failure, a standard Treatment-based, Phase II, double-blind, multicenter, placebo-controlled, standard-of-care-based trial The study was conducted at multiple clinical sites in China. A total of 195 patients with NYHA class II or III Stable patients with chronic heart failure were admitted to the hospital and divided into three groups: placebo, 0.6 μg / kg The groups were randomly assigned to receive either rhNRG-1 or rhNRG-1 at 1.2 μg / kg. There were no significant differences in demographics or treatment history between the two groups. The patients were administered the drug for 10 consecutive days in the hospital and were discharged after the 11th follow-up. Another follow-up visit was conducted at 30 and 90 days after the last patient was admitted. A telephone interview was conducted one year later.

[0067] Investigational drug: Specifications: Neucardin™, molecular weight of 7054 Dal (1 μg = 0.14 nm) 61 amino acid sequence containing the EGF-like domain of the neuregulin-1 β2 isoform of ol Acid polypeptide. 250 μg (5000 EU) / vial (1 μg = 20 EU).

[0068] Preparation: For injection.

[0069] Administration form: Infusion.

[0070] Storage: 3-8°C, limited use, in a safe place away from light.

[0071] placebo: Specifications: Neucardin™ excipient (active recombinant human neuregulin-1 protein) Protein-free 250 μg / vial).

[0072] [Table 5]

[0073] Test Procedure Criteria for study participation included a relatively stable disease state (no clinical signs, symptoms, or symptoms for more than 1 month) LVE (including those receiving acceptable standard treatment for CHF at target or maximum tolerated doses) Patients with CHF (NYHA class II or III) between the ages of 18 and 65 years old with an F of 40% or less The main exclusion criteria included acute myocardial infarction, hypertrophic cardiomyopathy, constrictive pericarditis, severe Valvular or congenital heart disease, severe pulmonary hypertension, systolic blood pressure lower than 90 mmHg or systolic blood pressure higher than 160 mmHg, severe arrhythmia, cardiac arrest within the past 6 months Female patients who had undergone surgery or had a cerebrovascular event, were claustrophobic, or were pregnant were included. All patients signed a consent form.

[0074] Placebo or rhNRG-1 (0.6 or 1.2 μg / kg / day) for 10 consecutive days Patients were randomly assigned to one of three groups to receive 100 mg of riboflavin and were discharged after 11 days of follow-up. Two separate follow-up visits were conducted on the 30th and 90th days. Blood samples were collected from each patient on days 1, 30, and 90. NT-proBNP NT-proBNP was measured at the core laboratory using a Biomedica kit. One year after the last patient was admitted, a telephone interview was conducted to collect information on readmissions. All telephone interviews were recorded on a special form signed by the researcher. Ta.

[0075] Of 48 patients in the placebo group with available readmission information, 12 (25.0%) patients were re-hospitalized at least once due to worsening heart failure. In the / kg group, only 4 of 46 patients (8.7%) were readmitted to the hospital (P = 0.05 compared with placebo); readmission rate in the 1.2 μg / kg group was 2 The mean number of readmissions was 2.0% (11 / 50) per patient in the placebo group. The mean values ​​were 0.458 (22 / 48) per 1000 mg / kg group, 0.6 μg / kg group (8 / 41), and 1.0 μg / kg group (8 / 41). In the 0.2 μg / kg group (19 / 50), the mean number of rehospitalizations was significantly lower than in the placebo group. This represents a decrease of 57.4% and 17.0%, respectively.

[0076] In the placebo group, NT-proBNP remained almost constant throughout the study compared with baseline. On day 11, NT-proBNP levels were significantly higher in the rhNRG-1 group. In the 0.6 μg / kg group, the mean values ​​increased from 1853 ± 1512 to 2399 ± 1841. fmol / ml, P<0.01; 1.2 μg / kg group, 1562 ± 1275 (From 2774±1926 fmol / ml, P<0.01). However, this increase was temporary. This is not due to a deterioration in cardiac function, as cardiac function has been improved. In the 1.2 μg / kg group, NT-proBNP was significantly higher at 30 and 90 days. Furthermore, in the 0.6 μg / kg group, the In comparison, NT-proBNP was 1323 ± 1124 fmol / ml at day 30 (P = 0 .01) and at 90 days (1518 ± 1403 fmol / ml, P = 0.01). It has decreased.

[0077] These results suggest that treatment with rhNRG-1 reduces rehospitalization and increases NT-proBNP levels. rhNRG-1 provides long-term benefits to patients with chronic heart failure by lowering plasma levels It showed that it can be done.

[0078] Example 3: Recombinant Human Neuregulin 1 in Patients with Chronic Heart Failure Based on Standard of Care Randomized, double-blind, multicenter, placebo-controlled survival study To evaluate the effect of recombinant human neuregulin-1 infusion on chronic heart failure compared with standard of care Based on this, a phase II, double-blind, multicenter, placebo-controlled study was conducted at multiple clinical centers in China. A total of 351 patients with stable chronic heart failure (NYHA class III or IV) were included. were admitted to hospital and randomized to placebo or rhNRG-1 group (0.6 μg / kg). There were no significant differences in demographics or treatment history between the groups. According to the protocol, patients were administered the drug for 10 consecutive days in the hospital, with a follow-up on the 11th day. They were subsequently discharged and treated as outpatients once a week from week 3 to week 25. Blood samples were taken from each patient before (baseline) and at each follow-up visit. NT-proBNP was measured using the T-proBNP measurement method (Biomedica kit). P was examined at a core laboratory. Survival information was collected at week 52 of the study.

[0079] Investigational drug: Specifications: Neucardin™, molecular weight of 7054 Dal (1 μg = 0.14 nm) 61 amino acid sequence containing the EGF-like domain of the neuregulin-1 β2 isoform of ol Acid polypeptide. 250 μg (5000 EU) / vial (1 μg = 20 EU).

[0080] Preparation: For injection.

[0081] Administration: Infusion or intravenous infusion.

[0082] Storage: 3-8°C, limited use, in a safe place away from light.

[0083] placebo: Specifications: Excipient of Neucardin™. 250 μg / vial, containing the active ingredient Does not contain recombinant human neuregulin-1 protein.

[0084] [Table 6]

[0085] Criteria for study participation included a relatively stable disease state (no clinical signs, symptoms, or symptoms for more than 1 month) LVE (including those receiving acceptable standard treatment for CHF at target or maximum tolerated doses) Patients with CHF (NYHA class III or IV) between the ages of 18 and 80 years old with an F of 40% or less The main exclusion criteria included acute myocardial infarction, hypertrophic cardiomyopathy, constrictive pericarditis, severe Valvular or congenital heart disease, severe pulmonary hypertension, systolic blood pressure lower than 90 mmHg or systolic blood pressure higher than 160 mmHg, severe arrhythmia, cardiac arrest within the past 6 months Female patients who had undergone surgery or had a cerebrovascular event, were claustrophobic, or were pregnant were included. All patients signed a consent form.

[0086] The all-cause mortality rate at week 52 in the placebo group was 15.91% (176 patients). 28 patients died, while the all-cause mortality rate in the rhNRG-1 group was 9.71%. Of the 175 patients who completed the study, 16 died (hazard ratio = 0.425, 95 %CI 0.222-0.813, p=0.0097). Mortality from cardiovascular events When the placebo group was examined, the mortality rate at week 52 was 14.77%, with 176 patients Of these, 26 died, compared with 9.71% in the rhNRG-1 group. The placebo group continued conventional standard treatment for chronic heart failure, but the patients receiving rhNRG-1 showed no significant improvement. The mortality rate was found to be approximately 40% lower than in the placebo group.

[0087] All-cause mortality based on baseline NT-proBNP stratification was also analyzed. -proBNP level ≤1600 fmol / ml, >1600 fmol / ml and below 4000 fmol / ml, or above 4000 fmol / ml. When divided, the mortality rate in the rhNRG-1 group compared with the placebo group was 1. .49% vs. 8.49%, 8.96% vs. 23.33%, and 26.67% vs. 28.00% NT-proBNP levels were kept below 4000 fmol / ml or 4000 fmol / ml. When stratified by ≥ 100 mg / mL, the prognosis for mortality in the rhNRG-1 group was Mortality rates in the placebo group were 5.22% vs. 14.89%, respectively (p=0.0092); and 26.67% vs. 28.00%. These results suggest that rhNRG-1 is effective in patients with chronic heart failure. These results demonstrate statistical significance in demonstrating that treatment with steroids can substantially improve patient survival.

[0088] Additionally, patients were classified as having a baseline NYHA cardiac function class of III or IV. Class III all-cause mortality was 6.06% (1.06%) in the rhNRG-1 group. 8 deaths in 32 patients) and 15.49% in the placebo group (142 patients) 22 of these died (p=0.0189). On the other hand, the all-cause mortality rate in class IV was The rhNRG-1 group had a 20.93% (9 deaths out of 43 patients) and the pro 17.65% (6 deaths out of 34 patients) in the placebo group (p=0.7789) is.

Claims

1. A pharmaceutical composition for use in treating chronic heart failure, comprising: the pharmaceutical composition comprises a neuregulin; The above treatment methods are a) measuring the patient's plasma level of NT-proBNP prior to treatment; b) administering the pharmaceutical composition to the patient only when, based on the result of the measurement in a), the plasma level of NT-proBNP is 4000 fmol / ml or less; The pharmaceutical composition is administered to the patient at a dose of 0.6 μg / kg / day of the neuregulin.

2. The pharmaceutical composition described in claim 1, characterized in that the pharmaceutical composition is administered when the patient's cardiac function is classified as NYHA class II or III according to the NYHA cardiac function classification.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition is administered when the measured plasma level of NT-proBNP based on the result of step a) is (1) between 1600 fmol / ml and 4000 fmol / ml, or (2) 1600 fmol / ml or less.

4. A pharmaceutical composition described in any one of claims 1 to 3, characterized in that the plasma level is measured by an immunoassay method.

5. A pharmaceutical composition described in any one of claims 1 to 4, characterized in that the neuregulin is neuregulin-1, or the neuregulin includes the EGF-like domain of neuregulin-1, or the neuregulin includes the amino acid sequence of SEQ ID NO:

1.

6. A pharmaceutical composition described in any one of claims 1 to 5, characterized in that the chronic heart failure is ischemic, congenital, rheumatic, idiopathic, viral, or toxic.

7. A pharmaceutical composition described in any one of claims 1 to 6, characterized in that the pharmaceutical composition is administered to the patient in an induction regimen.

8. The pharmaceutical composition described in Claim 7, characterized in that the induction regimen includes administering the pharmaceutical composition for at least 3, 5, 7 or 10 consecutive days.

9. The pharmaceutical composition described in Claim 7, characterized in that the pharmaceutical composition is administered to the patient in a management regimen after the induction regimen.

10. The pharmaceutical composition of claim 9, characterized in that the management regimen includes administering the pharmaceutical composition every 3, 5, 7 or 10 days.

11. The pharmaceutical composition described in any one of claims 1 to 10, characterized in that the neuregulin is administered to the patient by intravenous infusion.

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