Methods and compositions for preventing, treating, or delaying heart failure using neuregulin.

Abstract

This invention provides the application of neuregulin protein in the manufacture of drugs for preventing, treating, or delaying human heart failure, and methods for using such drugs. [Solution] The method includes: first examining the patient before treatment, wherein the examination includes detecting plasma levels of NT-proBNP or BNP; and subsequently providing appropriate treatment based on the examination results. If the examination results are within the optimal therapeutic range, the patient is suitable for treatment of heart failure by administering an effective dose of Neureglin.

Description

Technical Field

[0001] (Field of the Invention) The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure. The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure. The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure. The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure. The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure. The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure. The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure. The present invention relates to the application of neuregulin in the manufacture of a medicament for preventing, treating or delaying human heart failure and a method for administering said medicament therefor. In particular, the present invention provides a method for preventing, treating or delaying human heart failure by administering a medicament containing neuregulin to a specific population of patients with heart failure. In particular, the present invention provides a method for treating heart failure using a medicament containing neuregulin. The method involves making an appropriate treatment decision for the patient based on pre-treatment tests and test results. When the results of the pre-treatment tests are within the optimal treatment range, it is appropriate to administer an effective dose of neuregulin to patients with heart failure.

Background Art

[0002] (Background of the Invention) Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3% - 4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3% - 4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3% - 4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3%-4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3% - 4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3% - 4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3% - 4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Heart failure (HF) is a syndrome associated with heart dysfunction caused by various heart diseases. The main treatment for patients with HF, angiotensin-converting enzyme (ACE) inhibitors, are effective in dilating blood vessels, reducing blood pressure and reducing heart load. Despite the statistically significant reduction in the mortality rate (%) of patients treated with ACE inhibitors, the actual reduction in mortality is only an average of 3% - 4%, and there is also a potential for some side effects. There are also limitations to other preventive or treatment options for HF. For example, heart transplantation is inevitably more costly and invasive than drug therapy, and is also limited by the availability of heart donors. In addition, treatment options using mechanical devices such as biventricular pacemakers are also invasive and costly. Because existing therapies have shortcomings, new treatments are urgently needed.

[0003] A promising new therapy involves molecules also known as glial growth factors (GGF) or novel differentiation factors (NDF). Neuregulin (NRG), neuregulin, and heregulin (HR) are glucoproteins with a volume of 440 kD. G)) Including administration to patients with HF or patients at risk of HF; NRG is intercellular It is a protein involved in signal transduction and is linked to the ErbB family of receptor tyrosine kinases. It acts as a binding ligand. The NRG family consists of four members: NRG1, NRG2, and NRG3. It consists of , and NRG4 (Falls et al., Exp Cell Res. 284:14-30, 2003). NRG is used in various biological processes. Somatic response: Stimulation of differentiation of breast cancer cells and production of milk proteins, and conversion of nerve corona cells to Schwann cells. Induction of differentiation, stimulation of acetylcholine receptor synthesis in skeletal muscle cells, and cardiomyocytes It is involved in survival and promoting DNA synthesis. Homozygous macules with severe neuroregulin deficiency. In vivo studies in embryos have shown that neuregrin is essential for the development of the heart and nervous system. It was shown that NRG1 plays an important role in the development of the nervous system, heart, and mammary glands. Several pieces of evidence suggest that NRG1 signaling is involved in the development and function of some other organs / systems. Furthermore, it is suggested that it plays a role in the development of human diseases (such as schizophrenia and breast cancer). NRG1 exists in multiple isoforms. Genetic mutant mice (gene knockout mice) Research results in mice showed that the in vivo function of the isoform is its N-terminal region or epithelium. It is suggested that the growth factor (EGF)-like region may differ. This invention relates to neuregulin 1β (NRG Based on -1β).

[0004] Neuregulin 1β is a transmembrane protein (Holmes et al., Science 256, 1205-121). (0, 1992). The extramembrane portion, which includes the Ig-like domain and EGF-like domain, is the N-terminus, and the intramembrane portion is the C-terminus. It is the edge. Under the action of extracellular matrix metalloproteinases, the extracellular membrane of neuregrin The portion can be cleaved by enzymes and become free. This allows it to surround the neuregrin. Binding to ErbB receptors on the cell surface is promoted, and the corresponding cell signaling is activated. ru.

[0005] The ErbB family also has four members: ErbB1, ErbB2, ErbB3, and ErbB4. They are all transmembrane proteins with a molecular weight of approximately 180-185 kD, with the exception of ErbB2. And all of them contain a ligand-binding domain at their extramembrane N-terminus; with the exception of ErbB3, All of these intramembrane C-terminuses possess protein tyrosine kinase activity. ErbB1 is involved in epidermal proliferation. While EGFR receptors are neuroregulin receptors, ErbB3 and ErbB4 are neuroregulin receptors. Of the neuroregulin receptors, only ErbB2 and ErbB4 are highly expressed in the heart (Yarden et al.) Literature, Nat Rev Mol Cell Biol, 2:127-137, 2001).

[0006] When neuregulin binds to the extramembrane portion of ErbB3 / ErbB4, other ErbB facilli of ErbB3 / ErbB4 Heterodimerization with reamers (often including ErbB2) or homodimerization of ErbB4 itself This can occur, and these processes are responsible for phosphorylation of the membrane interior (Yarden et al., Nat Rev Mol Cell Bi (ol,2:127-137,2001). The phosphorylated intramembrane portion consists of multiple intracellular signaling proteins. It can further bind to the cell, thereby activating the downstream ERK or AKT signaling pathway. A series of cellular responses, including stimulation or inhibition of proliferation, apoptosis, migration, differentiation, or cell adhesion. This is caused.

[0007] Neuregulin is especially essential for cardiac development (WO0037095, CN1276381, WO03099300) WO9426298, US6444642, WO9918976, WO0064400, Zhao et al., J.Biol.Chem.273,1026 1-10269, 1998). In early embryonic development, neuregulin expression is mainly limited to the endocardium; Uregrin is then released to surrounding cardiomyocytes via the paracrine pathway, blocking the cell membrane tannins. The extramembrane portion of the protein tyrosine kinase receptor ErbB4 binds, and ErbB4 subsequently binds to ErbB2. It forms a heterodimer. The formation and activation of the ErbB4 / ErbB2 complex occurs in the early cavernous heart. Essential for the formation of cardiac trabeculae. Neuregrin, ErbB4, and ErbB2 are all present. If the gene is missing, the trabeculae of the fetus in the womb are lost during early development, leading to death. WO0037095 According to this study, a certain concentration of neuregrin continuously activates the ERK signaling pathway, and the myocardium Promotes cell proliferation and differentiation, and sarcomereal septa and cell frames in cardiomyocytes and cell adhesion. It can lead to the restructuring of the workpiece, improve the structure of cardiomyocytes, and strengthen cardiomyocyte contraction. Furthermore, WO0037095 and WO003099300 contain neuregulin, which is used in the detection of many cardiovascular diseases. It is stated that it can be used for diagnosis and treatment.

[0008] The following lists some prior art documents related to the present invention: 1. Myocardial function and manipulation : WO0037095, 2. Novel applications of the growth factor neuregulin and its analogs: CN1276381; 3. Neuregulin-based methods and compositions for treating cardiovascular diseases: WO03099300; 4. Zh ao YY, Sawyer DR, Baliga RR, Opel DJ, Han X, Marchionni MA and Kelly RA, "Neuregulins Promote Survival and Growth of Cardiac Myocytes." J. Biol. Chem. 273, 10261-10269 (1998); 5. Methods for treating muscle diseases and disorders : WO9426298; 6. Methods for increasing myotube formation or survival or mitogenesis, differentiation, or survival of muscle cells using neuregulin: US6444642. 7. Therapeutic methods involving the use of neuregulin: WO9918976; 8. Therapeutic methods for congestive heart failure: WO0064400; 9. Ho lmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD et al., "Identification of heregulin, a specific activator p185erbB2." Science 256, 1205-1210 (1992); 10. Fa lls DL, "Neuregulins: function, form, and signaling strategies." : WO9918976; 8. Therapeutic methods for congestive heart failure: WO0064400; 9. Ho lmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD et al., "Identification of heregulin, a specific activator p185erbB2." Science 256, 1205-1210 (1992); 10. Fa lls DL, "Neuregulins: function, form, and signaling strategies." : WO9918976; 8. Therapeutic methods for congestive heart failure: WO0064400; 9. Ho ctions, forms and signaling strategies.)” Experimental Cell Research, 284, 14-30(2 003).11. The literature by Yarden Y and Sliwkowski X, "Unraveling the ErbB signaling network ( "Untangling the ErbB signaling Network.)" Nature Reviews: Molecular Cell Biology, 2 127-137 (2001).

[0009] Research has shown that the EGF-like domain of NRG1 has approximately 50-64 amino acids and binds to these receptors. It has been shown that together these are sufficient to activate them. Previous research has shown that new Regulin-1β (NRG-1β) has been shown to be able to directly bind to ErbB3 and ErbB4 with high affinity. The orphan receptor ErbB2 has a higher affinity for ErbB3 or ErbB4 than for homodimer formation. It can also form heterodimers with ErbB3 or ErbB4 with high affinity. Results from neurodevelopmental studies The formation of the sympathetic nervous system requires a complete NRG-1β, ErbB2, and ErbB3 signaling pathway. This was suggested. Targeted destruction of NRG-1β, ErbB2, or ErbB4 resulted in Due to the developmental defects of the heart, it is lethal to the fetus. Also, recent studies have shown that heart blood The importance of NRG-1β, ErbB2, and ErbB4 in the development of the vascular system and the maintenance of normal cardiac function in adults. Its role was emphasized. NRG-1β can enhance the tissue structure of sarcomeres in adult cardiomyocytes. This was shown. Administration of recombinant NRG-1β EGF-like domains resulted in cardiomyopathy in various HF animal models. It may significantly improve or prevent functional decline, and similar results have been observed in clinical trials. However, the method of use of this product or composition and the superior treatment in some subgroups More research is needed to clarify how to obtain therapeutic effects. In this invention, New The present invention provides a method for treating heart failure using a pharmaceutical product containing regulin. The method includes pre-treatment examinations and This involves determining the appropriate treatment for the patient based on the results of pre-treatment tests. If within the therapeutic range, administering an effective dose of neuregulin to a patient with heart failure is... That is appropriate. [Overview of the Initiative]

[0010] (Summary of the invention) (A. A brief overview) During the clinical trial of the treatment of HF with Neuregulin, the applicant in this case was Neuregulin Therapy is graded according to the functional classification of the New York Heart Association (NYHA) or based on the patient's plasma NT-p Significant treatment in HF patients screened by roBNP or BNP level measurement It was discovered that the treatment achieved efficacy. These treatment outcomes included a significant reduction in mortality. These treatment outcomes included a significant reduction in readmissions for treatment. Furthermore, the study showed that Furthermore, in various animal models of HF and in patients with HF, NRG significantly reduced myocardial function. It has been shown to improve or prevent the following: Neureglin, Neureglin polypeptide, Ni Contains neuregulin variants, neuregulin derivatives, and NRG-like functional domains (multiple domains are possible). All compositions, or compounds having similar activity to neuregulin, fall within the scope of the present invention. ru.

[0011] In a first aspect of the present invention, the present invention comprises an effective dose of neuregulin for the treatment of heart failure. A drug composition is provided. Patients treated with this drug composition achieve remarkable therapeutic results. It was achieved. In several embodiments, the therapeutic effect manifested as a significant reduction in mortality. In several embodiments, the therapeutic effect manifested as a significant reduction in readmissions for treatment. In some embodiments, the therapeutic effect manifests as a decrease in biomarker levels, and chronic It showed that the heart failure was improved. In some embodiments, the drug composition was derived It was administered to the patient for the introductory regimen. In some embodiments, the introductory regimen is small It included repeated administration of the drug composition over at least 3, 5, 7, or 10 consecutive days. In several preferred embodiments, the drug composition is administered at least 3, 6 times after the induction regimen. This was maintained over 12 months. In some preferred embodiments, the maintenance regime is 3 The drug composition was administered every 5, 7, or 10 days. In a preferred embodiment, In the HF patient being treated, the patient was female. In a preferred embodiment, the HF patient being treated was female. Female HF patients with plasma NT-proBNP levels of 3000 fmol / ml or less, and plasma NT-proBNP In a preferred embodiment, treatment was administered to a male HF patient with a P level of 1600 fmol / ml or less. The HF patients included in the study were female HF patients with plasma NT-proBNP levels of 3000 fmol / ml or less.

[0012] In another aspect of the present invention, the method has the effect of improving the survival rate or reducing the mortality rate of patients with chronic HF. The method involves administering a drug composition containing an effective dose of neuregulin to patients with chronic HF. In several embodiments, the drug composition was administered to the patient for an induction regimen. In one preferred embodiment, the initiation regimen is for at least 3, 5, 7, or 10 consecutive days The procedure involved repeated administration of the drug composition over time. In some preferred embodiments, The administration of the drug composition was maintained for at least 3, 6, or 12 months after the induction regimen. In a preferred embodiment, the maintenance regimen involves administering the drug composition every 3, 5, 7, or 10 days. It included giving. In a preferred embodiment, the HF patient being treated was female. In a preferred embodiment, the HF patient being treated has a plasma NT-proBNP level of 3000 fMo. Female HF patients with a plasma NT-proBNP level of ≤1 / 100 fmol / ml, and male patients with a plasma NT-proBNP level of ≤1600 fmol / ml. The patient was an HF patient. In a preferred embodiment, the HF patient being treated had a plasma NT-proBNP level The patient was a female HF patient with a Bell's blood count of 3000 fmol / ml or less.

[0013] In another aspect of the present invention, information is provided regarding the application of neuregulin in drug preparations. The drug may provide long-term benefits to patients with chronic heart failure. In one embodiment, long The immediate benefit is an improvement in survival rates. In one aspect, the long-term benefit is a reduction in readmission rates. This means a decrease. In another embodiment, the long-term benefit is an improvement (decrease) in biomarkers. This means that the long-term prognosis of HF can be predicted. In some embodiments In some preferred embodiments, the drug was administered to the patient for the induction regimen. In this case, the introductory regimen involves repeated administration of the drug over at least 3, 5, 7, or 10 consecutive days. This includes. In some preferred embodiments, the patient has at least 3 days after the introduction regimen. Maintenance doses were administered for 6 or 12 months. In some preferred embodiments, maintenance doses were administered. Dimen contained drug administration every 3, 5, 7, or 10 days. In a preferred embodiment, The HF patient being treated was female. In a preferred embodiment, the HF patient being treated had blood Female HF patients with serum NT-proBNP levels of 3000 fmol / ml or less, and plasma NT-proBNP levels The patient was a male HF patient with a bell filtration rate of 1600 fmol / ml or less. In a preferred embodiment, the treatment was The HF patients were female HF patients with plasma NT-proBNP levels of 3000 fmol / ml or less.

[0014] In another aspect of the present invention, HF patients suitable for treatment with neuregulin are screened A method for [specific purpose] is provided. The method includes measuring the patient's NT-proBNP plasma level. In this embodiment, an NT-proBNP plasma level of 4000 fmol / ml or less indicates that HF ​​patients have neuregulin It has been demonstrated that it is suitable for treatment. In another embodiment, 1600 fmol / ml~4 NT-proBNP plasma levels within the range of 000 fmol / ml indicate that the patient's HF is being treated with neuregulin. It was shown to be suitable. In another embodiment, NT-proBNP plasma levels of 1600 fmol / ml or less This demonstrated that the patient's HF was suitable for treatment with Neureglin. In another preferred embodiment... In female HF patients with NT-proBNP plasma levels of 3000 fmol / ml or less, HF is neutrophilized. - It has been shown to be suitable for treatment with Regulin. In another preferred embodiment, 3000 fm Female HF patients with NT-proBNP plasma levels of less than 1600 fmol / ml and NT-proBNP plasma levels of less than 1600 fmol / ml Male HF patients with serous levels were shown to be suitable for treatment with Neureglin. In a preferred embodiment, female HF patients, regardless of NT-proBNP plasma levels, It has been shown to be suitable for treatment with Regulin.

[0015] In another aspect of the present invention, HF patients suitable for treatment with neuregulin are screened This provides a method for performing the procedure. The method follows the functional classification of the New York Heart Association (NYHA). This includes evaluating the patient's cardiac function. In one embodiment, NYHA Class II is defined as the patient's HF is It was shown to be suitable for treatment with Neureglin. In another embodiment, NYHA class II Study I showed that the patient's HF was suitable for treatment with neuregulin.

[0016] In another aspect of the present invention, the method provides treatment for chronic heart failure with neuregulin. The method involves a pre-treatment evaluation procedure and the evaluation results for patients receiving treatment with Neureglin. This includes determining the eligibility of the person. In some embodiments, the evaluation procedure includes the assessment of NY in patients with chronic HF. This included grading of HA functional classes. In another embodiment, the evaluation procedure included all chronic HF This included determining the patient's plasma NT-proBNP or BNP levels.

[0017] In another aspect of the present invention, screening of HF patients suitable for treatment with neuregulin A diagnostic reagent kit for HF is provided. In one embodiment, the reagent kit provides NT-p for HF patients. Includes one or more immunoassay reagents for measuring roBNP plasma levels below 4000 fmol / ml. The level indicates that the patient is suitable for treatment of HF with Neureglin. In another embodiment... Furthermore, NT-proBNP plasma levels within the range of 1600 fmol / ml to 4000 fmol / ml indicate that the patient's HF is new It was shown to be suitable for treatment with Regulin. In another embodiment, N1600 fmol / ml or less T-proBNP plasma levels indicated that the patient's HF was suitable for treatment with Neureglin. In a preferred embodiment, female HF patients having NT-proBNP plasma levels of 3000 fmol / ml or less It has been shown that HF ​​in these individuals is suitable for treatment with Neureglin.

[0018] In another embodiment of the present invention, an accompanying diagnostic method for the treatment of chronic HF with neuregulin. We provide diagnostic testing. N-terminal brain natriuretic peptide (NT-proBNP) for diagnostic testing. It is used as a biomarker. In some embodiments, the amount is less than 4000 fmol / ml. Bell demonstrated that the patient's HF was suitable for treatment with Neureglin. In another embodiment... Furthermore, a level of 1600 fmol / ml to 4000 fmol / ml indicates that the patient's HF is suitable for treatment with Neureglin. This demonstrated that. In another embodiment, NT-proBNP plasma levels below 1600 fmol / ml are The patient's HF was shown to be suitable for treatment with Neureglin. In another preferred embodiment... Furthermore, in female HF patients with NT-proBNP plasma levels of 3000 fmol / ml or less, HF is new It has been shown to be suitable for treatment with Regulin.

[0019] In another aspect of the present invention, eligibility for HF patients receiving treatment with Neureglin is determined. An accompanying diagnostic kit is provided for this purpose. The accompanying diagnostic kit includes plasma NT-proBNP or BNP level A reagent kit for determining the appropriate level of neuregulin treatment for patients, and the appropriate level of neuregulin treatment for patients based on the test results. Includes instructions for determining the specifications.

[0020] In another aspect of the present invention, a kit is provided. The kit contains an effective dose of neuregulin Includes one or more containers. Proteins may be provided alone or with other compatible drugs / substances. They may be combined to form a composition. Preferred drug dosage forms are sterile saline, glucose It can be used in combination with a solution, buffer, or other compatible sterile solution. Optionally, The composition may be freeze-dried or dried. In one embodiment, the kit of the present invention is Needles or syringes for injection, preferably in sterile packaging, and / or packaged alcohol cots Further comprising alcohol cotton balls. In another embodiment, in the present invention The kit may include instructions for the doctor or patient regarding the use of the drug composition, depending on the situation. Instructions for use are further included. In another preferred embodiment, the kit of the present invention is effective The diagnostic kit includes a dose of NRG and a reagent kit, and measures NT-proBNP plasma levels in HF patients. Includes one or more immunoassay reagents for the purpose.

[0021] In another embodiment of the present invention, Neuregrin contains NT-proBNP in a therapeutically appropriate range before treatment. Administer at an effective dose to chronic HF patients with plasma levels. In one embodiment, appropriate for treatment. The appropriate range was 4000 fmol / ml or less. In another embodiment, the appropriate range for treatment was 1600 fmol / ml. The range was l / ml to 4000 fmol / ml. In another embodiment, the appropriate range for treatment was 1600 fmol / ml or less. Below. In another preferred embodiment, a range of female HF patients suitable for treatment. It was 3000 fmol / ml or less. In another preferred embodiment, the plasma level was immunoassay It was decided by I.

[0022] In another aspect of the present invention, neureglin's cardiac function is associated with the New York Heart Association (N It is administered at an effective dose to chronic HF patients graded according to the functional classification of the YHA. Several implementations In some embodiments, the specific functional class was NYHA class II. The specific functional class was NYHA Class III. [Modes for carrying out the invention]

[0023] (B.Definition) Unless otherwise defined, all technical terms used herein refer to the art of the invention. It has the same meaning as understood by the average engineer. All patent documents, patents Application documents, published patent documents, and other publications are incorporated herein by reference in their entirety. The definitions described herein do not necessarily correspond to the corresponding definitions in any of the above references. In the event of any inability to comply or any conflict, the definitions herein shall prevail.

[0024] Unless explicitly stated in the context, all singular and plural determiners / nouns (e.g., a, a) n, the, these, etc. are interchangeable, and "at least one" and "one or more" are interchangeable.

[0025] As used herein, "neureglin" or "NRG" refers to ErbB2, ErbB3, ErbB4 or the same. Proteins or polyphosphates that bind to and activate the heterodimers or homodimers of these molecules. A lipeptide, consisting of a neureglin isoform and an EGF-like domain of neureglin. , polypeptides containing neuregrin EGF-like domains(s), neuregrinvarian Neuregrin-like genes or derivatives, and other neuregulin-like genes capable of activating the above receptor. This refers to the protein or polypeptide containing the product. Furthermore, Neuregrin is NRG1, NRG2, NRG3, and NRG4 proteins, polypeptides, fragments, and complexes having NRG-like function It contains. Preferably, neuregrin binds to an ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimer. and a protein or polypeptide capable of activating these. To refer to an explanatory example rather than an example, the neuregrin of the present invention is NRG-1β2 isophore It is a fragment of the EGF-like domain, specifically a fragment of amino acids at positions 177 to 237, which contains the EGF-like domain. The fragment has the following amino acid sequence: [ka] The neuregrin used in this invention activates the above receptors and regulates their biological functions. It can be linked; for example, neuregrins are acetylcholine receptors in skeletal muscle cells. It can stimulate the body's synthesis and promote the differentiation, survival, and DNA synthesis of cardiomyocytes. Neuregulin contains conservative mutations that have virtually no effect on the protein's biological function. There is a neuroregulin variant that has [this characteristic]. It is well understood by general engineers in the field. As such, a single amino acid mutation in a non-critical region is generally a protein or It does not alter the biological function of polypeptides (Watson et al., "Molecular Biology of Genes (Mole See "Cycular Biology of the Genetics," 4th edition, 1987, The Bejacmin / Cummings Pub.co., p. 224. (Please be illuminated). The neuregrin used in this invention is isolated from a natural source, and It can be obtained through genetic engineering, artificial synthesis, or other approaches.

[0026] The terms "epidermal growth factor-like domain" or "EGF-like domain" used herein refer to Nuremell. Encoded by the Grin gene, ErbB2, ErbB3, ErbB4, or their heterodimers It can bind to or homodimers and activate them, as well as the following references. References: WO 00 / 64400, Holmes et al., Science, 256:1205-1210 (1992), U.S. 5,530,1 Issues 09 and 5,716,930, the literature of Hijazi et al., Int.J.Oncol.,13:1061-1067 (1998), Chang et al. References: Nature, 387:509-512 (1997), Carraway et al., Nature, 387:512-516 (1997) , as described in Higashiyama et al.'s literature, J. Biochem., 122:675-680 (1997), and WO 97 / 09425. This refers to polypeptide fragments that are structurally similar to the EGF receptor binding domain. In this embodiment, the EGF-like domain binds to an ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimer, These are activated. In some embodiments, the EGF-like domain is the receptor for NRG-1. Contains amino acids of the binding domain. In some embodiments, the EGF-like domain is NRG-1 Refers to amino acids at positions 177-226, 177-237, or 177-240. Several embodiments In this case, the EGF-like domain contains amino acids from the receptor-binding domain of NRG-2. In this embodiment, the EGF-like domain contains amino acids of the receptor-binding domain of NRG-3. In that embodiment, the EGF-like domain contains amino acids of the receptor-binding domain of NRG-4. In some embodiments, the EGF-like domain is as described in U.S. Patent No. 5,834,229. Mino acid sequence: Ala Glu Lys Glu Lys Thr Phe Cys Val Asn Gly Gly Glu Cys Phe Met Val Includes Lys Asp Leu Ser Asn Pro.

[0027] Dosage form, dosage and route of administration of neuregulin protein, and superior pharmaceutical composition form The state can be determined according to methods known in the art (for example, "Remington: Drug "Remington: The Science and Practice of Pharmacy," Alfonso R. Gen naro (ed.), Mack Publishing Company, 1997.4; "Therapeutic Peptides and Proteins: Formulations" , Processing and Delivery Systems (Therapeutic Peptides and Proteins: Formulation, Processing) g, and Delivery Systems), Banga, 1999; "Peptide and Protein Pharmaceutical Formulation Development (P ``harmaceutical Formulation Development of Peptides and Proteins'', Hovgaard and F. rkjr (ed.), Taylor & Francis, Inc., 2000; "Medical Applications of Liposomes" ns of Liposomes), Lasic and Papahadjopoulos (eds.), Elsevier Science, 1998, "Textbook of Gene Therapy," Jain, Hogrefe & Huber Publishers, 199 8; "Adenoviruses: Basic Biology to Gene Therapy" Gene Therapy), Vol. 15, Seth, Landes, Bioscience, 1999; Biopharmaceutical Drug Design and Drug Discovery ( "Biopharmaceutical Drug Design and Development," edited by Wu-Pong and Rojanasakul, Hu mana Press, 1999; “Therapeutic Angiogenesis: From basic science to clinical practice” From Basic Science to the Clinic), Vol. 28, Dole et al. (eds.), SpringerVerlag New Yo See rk, 1999.

[0028] Neuregrin protein can be administered orally, rectally, topically, by inhalation, buccal (sublingual), or parenterally (for example). It can be prepared for administration via subcutaneous, intramuscular, intradermal, or intravenous, transdermal, or other appropriate route. Of all these modes of administration, the most appropriate is the nature and severity of the disease, and This can be determined according to the characteristics of the specific neuroregulin protein used. Regulin protein may be administered alone; or more appropriately, as a drug-compatible carrier. Alternatively, it may be administered together with an excipient. Currently, any suitable drug can be used as an acceptable carrier or excipient. The modifier can be used in the current method (for example, "Remington: The Science and Practice of Pharmaceuticals"). ``Remington: The Science and Practice of Pharmacy'', Alfonso R. Gennaro (editor) Ma (See ck Publishing Company, April 1997).

[0029] According to the present invention, neuregulin protein alone or other media, carriers, or excipients are used. The various products manufactured using this method can be administered via intracavitary injection, subcutaneous injection, intravenous injection, intramuscular injection, or skin injection. It can be used via numerous suitable routes of administration, including internal injection, oral administration, or buccal administration. Ureglin is administered in single-dose forms in ampoules containing preservatives or in multi-dose containers. It can be used as a suspension, liquid, aqueous or buttery emulsion. It can be prepared in any dosage form, and a suspending agent, stabilizer, and / or dispersant can be added. This can be done; or, the active ingredient can be in powder form before use, and in a suitable medium, e.g. For example, dissolve in sterile, non-pyrogenic water or another solvent. The drug of the present invention is a topical product. When used as such, foaming compositions, gels, ointments, transdermal patches, or pasta, etc. It can be prepared as follows.

[0030] The acceptable components and modes of administration for the drug of the present invention are not limited to these, however U.S. Patent Nos. 5,736,154, 6,197,801B1, 5,741,511, 5,886,039, 5,941, This includes the components and forms published in Nos. 868, 6,258,374B1, and 5,686,102.

[0031] The size of the therapeutic dose for treatment or prevention depends on the severity of the condition being treated and the route of administration. They differ. Also, the dosage and possibly frequency of administration will depend on the individual patient's age, weight, condition, and It varies depending on the reaction.

[0032] The attending physician will determine when and how to discontinue or interrupt treatment if toxicity or adverse reactions occur. Please note that there is an obligation to know whether to discontinue or adjust / reduce the dosage. Conversely, if the clinical response is insufficient, when and how should the physician adjust the dose to a higher level? You should know that.

[0033] Any appropriate route of administration can be used. The drug is available in tablet, drug drop, and cachet forms. It can be made into dosage forms such as preparations, dispersants, suspensions, liquids, capsules, and patches. Please refer to "Remington's Pharmaceutical Sciences". In practical applications, Neuregrin protein, alone or in combination with other drugs, forms a close mixture. The active ingredient is then used as a pharmaceutical carrier or excipient according to conventional pharmaceutical compounding techniques, such as β-cyclodextrin. It can be combined with string and 2-hydroxypropyl-β-cyclodextrin. The carrier can be a preparation in a wide range of forms suitable for topical or parenteral administration. In the preparation of compositions for parenteral dosage forms such as internal injection or intravenous solution, similar compositions known to those skilled in the art are used. By utilizing pharmaceutical media, water, glycol, oil, buffering agents, sugars, preservatives, liposomes, etc. This is possible. Examples of such parenteral compositions include, but are not limited to, dextrose. There are 5% w / v saline, standard physiological saline, or other solutions. The neuregulin protein to be administered The total dose, either alone or in combination with other drugs, is approximately 1 ml to 2000 ml of intravenous fluid. It can be administered via Ial. The volume of the diluent will vary depending on the total dose to be administered.

[0034] Furthermore, the present invention provides a kit for implementing a treatment regimen. The kit contains an effective Contains one or more containers of the prescribed dose of neuregulin protein. The protein can be taken alone or in combination with other ingredients. It can be provided in combination with other acceptable drugs / substances for forming the substance. The appropriate pharmaceutical form is sterile saline solution, dextrose solution, or buffer solution, or other medical Combine with a sterile solution that is acceptable as a medicine. Alternatively, freeze-dry or dry the composition. It can be made possible; in this case, the kit can optionally reassemble the complex in a container and dissolve it for injection. The solution further comprises, preferably, a sterile, pharmaceutically acceptable solution for forming a liquid. Examples of pharmaceutically acceptable solutions are physiological saline and dextrose solution.

[0035] In this specification, “therapy” or “treatment” means that the symptoms of a condition, disorder or disease are improved, This refers to any form of change that is otherwise beneficial. The effect is to completely eliminate the disease or its symptoms. Or it is preventive in the sense of partially preventing the disease and / or is attributable to the disease It may be therapeutic in terms of partially or completely curing the harmful effects. Furthermore, the treatment is effective in its original form. This encompasses all medicinal uses of the compositions listed below.

[0036] As used herein, "heart failure" refers to a condition in which the heart does not pump blood at the rate required by metabolic tissues. It means an abnormality in cardiac function. Heart failure encompasses a wide range of disease conditions, such as congestive heart failure. Myocardial infarction, tachyarrhythmia, familial hypertrophic cardiomyopathy, ischemic heart disease, idiopathic dilated cardiomyopathy, And myocarditis, etc. Heart failure is not limited to ischemic, congenital, rheumatic, etc. It can be caused by several factors, including illusory, toxic, or idiopathic forms. Cardiac hypertrophy is a serious medical condition that can be a precursor to congestive heart failure and cardiac arrest.

[0037] Unless otherwise specified in the context, the terms "protein" and "polypeptide" as used herein refer to the terms used herein. "Petido" and "peptide" have the same meaning.

[0038] Unless otherwise specified in the context, "plasma" and "serum" as used herein refer to the same thing. It means to change.

[0039] Unless otherwise specified in the context, "not more than" as used herein means This refers to "less than or equal to."

[0040] As used herein, “long-term benefits” refer to those observed in the short period following treatment or intervention. This refers to the benefits caused by treatment or intervention that cannot be performed. Therefore, the long-term benefits include improved survival rates, reduced readmissions, and biomarkers indicating long-term prognosis. Improvement is possible. In some embodiments, the observation period for benefits is approximately 6 months. In that embodiment, the benefit observation period is approximately one year. In some embodiments, The profit observation period is approximately 2 years. In another embodiment, the profit observation period is approximately 3 years. It's been 5 years, or even 10 years or more.

[0041] As used herein, “survival” means that an object remains alive or is likely to remain alive. It means a period or probability. It can also be expressed as survival time or survival rate. Survival is the period from the start of diagnosis or treatment until the end of life. This refers to the percentage of people who survive the subsequent given period. For each subject, treatment Alternatively, an extension of survival time resulting from the interference may be considered a benefit. In this regard, an extension of the average survival period or an increase in the survival rate can be considered a benefit.

[0042] As used herein, "re-hospitalization" refers to the number or frequency of a patient's hospitalization within a given period. This means that hospitalization is due to the same condition being treated, regardless of whether all other conditions are the cause. It may be caused by other factors. For each subject, a reduction in the number of readmissions within a given period is a benefit. It can be considered as such. And for the target group or large population, the total number of readmissions or the average number of readmissions can be determined. A decrease in numbers can be considered a benefit.

[0043] The terms "N-terminal brain natriuretic peptide" or "NT-proBNP" used herein are inactivated. This refers to residual N-terminal proBNP, the latter being hormones released mainly from cardiomyocytes in the left ventricular wall. BNP is a prohormone that is a natriuretic peptide with activity as a hormone. In response to stretching and tension, the prohormone proBNP is released as BNP and the remaining inactive N as a hormone. It is separated into T-proBNP by proteolytic cleavage.

[0044] Plasma levels of BNP and NT-proBNP are used in the daily management of suspected or established heart failure. It is a promising tool. Most of the information on the use of BNP and NT-proBNP in clinical practice Research is addressing its diagnostic characteristics and supporting the prognostic value of BNP and NT-proBNP. An increasing amount of evidence is available. NT-proBNP has a half-life in the blood approximately six times longer than BNP. Therefore, it is more widely used as a diagnostic or prognostic marker for heart failure. Plasma NT -proBNP levels can be analyzed using commercially available kits. For example, but are not limited to There are commercial kits available from Roche or Biomedica.

[0045] Both BNP and NT-proBNP levels in plasma are typically worse for both markers. Because the outcome is higher in patients with poor results, it is used for screening and prognosis of heart failure. Furthermore, it is useful in establishing the prognosis of heart failure. In this invention, BNP or NT-proBNP We found that plasma levels indicate that the patient is suitable for treatment of heart failure with neuregulin. It is.

[0046] The terms "New York Heart Association (NYHA) functional classification" or "NYHA" cardiac function are used herein. The heart failure classification is a simple way to classify the degree of heart failure. This classification is based on the patient's physical activity level. Patients are categorized into one of four groups based on the degree of restriction they are experiencing. The limitations / symptoms are related to normal breathing and varying degrees of shortness of breath and / or angina pain. I. Symptoms and limitations in normal physical activity, such as shortness of breath when walking or climbing stairs. II. No symptoms (mild shortness of breath and / or angina) and slight limitations during normal activity. Yes; III. Even lighter activities than normal, such as walking short distances (20-100m), can cause symptoms. This severely restricts activity and stabilizes only at rest; and in case IV, symptoms persist even at rest. The test involves severe limitations, usually in bedridden patients.

[0047] As used herein, “active units,” “EU,” or “U” can induce up to 50% of the maximum reaction. This refers to the quantity of the standard sample. In other words, in order to determine the active units of a given active agent, The EC50 must be measured. For example, if the EC50 of a certain batch of product is 0.1 pg That constitutes one unit. Furthermore, if you use 1 pg of the product, you should use 10 EU (1 / 0.1). Therefore, EC50 is any method known in the art, including the method employed by the present inventors. This can be determined. The determination of this active unit is for genetically modified products and clinical applications. This is important for quality control of drugs used, and products manufactured by different pharmaceutical companies and / or This makes it possible to quantify products with different batch numbers using a uniform standard.

[0048] The following describes the indirect linkage of NRG to cell surface ErbB3 / ErbB4 molecules and ErbB2 phosphorylation. Exemplary, rapid, highly sensitive, high-flux, and quantitative methods for determining the biological activity of NRG-1 through intermediaries. This is a typical method (for example, the literature by Michael D. Sadick et al., 1996, Analytical Biochemistry, 2 See 35:207-214 and WO03 / 099300.

[0049] In short, it is called the kinase receptor-activating enzyme-binding immunosorbent assay (KIRA-ELISA). This assay consists of two separate microtiter plates, one of which is used for cell culture. It is used for nourishment, ligand stimulation, and cell lysis / receptor solubilization, and the other plate captures the receptor. For use in phosphotyrosine ELISA. For analysis of NRG-induced ErbB2 activation. We developed an assay that utilizes the stimulation of intact receptors on the surface of the adherent breast cancer cell line MCF-7. The membrane protein was solubilized by Triton X-100 lysis, and was ErbB2 specific, and ErbB3 or Er The receptor is captured in ELISA wells coated with an antibody that does not cross-react with bB4. Next, the degree of receptor phosphorylation is quantified by anti-phosphotyrosine ELISA. A reproducible standard curve will be created using the EC50 of Grin β1 (177-244) at approximately 360 pM. HRG The same β1(177-244) sample was subjected to KIRA-ELISA and quantitative antiphosphotyrosine Western blotting. When analyzed using both methods, the results are very closely correlated with each other. (As described in this report) The assay is based on the interaction of HRG with ErbB3 and / or ErbB4, resulting in the tyrosine phosphate of ErbB2. It is possible to quantify the transformation in a specific way.

[0050] Most genetically modified drugs are proteins and polypeptides, therefore The activity is determined by the active site formed by their amino acid sequence or their three-dimensional structure. It can be determined that the activity titer of proteins and polypeptides does not correspond to their absolute quality. Therefore, it cannot be determined using units of weight, like the activity titer of chemical drugs. However, the biological activity of genetically modified drugs generally corresponds to their pharmacodynamic properties, given The titer determination system established through the biological activity can determine its titer units. Therefore, the biological The determination of activity can be part of the dosage setting process for biologically active substances, and may involve genetic engineering. It is an important component of quality control for genetically modified products and products used in clinical settings. It is important to determine bioactivity standards for quality control of drugs.

[0051] The amount of standard that can induce 50% of the maximum reaction is defined as the active unit (1 EU). Therefore, different Products manufactured by the same pharmaceutical company and products with different batch numbers are quantified using a uniform standard. It is possible. [Examples]

[0052] (Detailed description of the invention) (Embodiment 1: Recombinant human neureg in patients with chronic heart failure based on standard treatment) A randomized, double-blind, multicenter, placebo-controlled survival trial of phosphorus (Trial 209) Evaluating the efficacy of recombinant human neuregulin (rhNRG-1) for injection in the treatment of chronic heart failure. To that end, a Phase II double-blind, multicenter, placebo-controlled, standard-of-care-based trial was conducted in multiple clinical settings in China. The study was conducted at a hospital center. A total of 351 patients with NYHA class III or class IV chronic heart failure participated. Participants were enrolled and randomized to either a placebo group or an rhNRG-1 group (0.6 μg / kg). Demographic and other factors were observed between the groups. There was no significant difference in background treatment. Patients were hospitalized and treated sequentially as planned. The patient was administered medication for 10 days and discharged on the 11th day. From week 3 to week 25, the patient was discharged. The patient received the medication once a week in the ward. Blood samples were taken from the patient before treatment and after each administration. The following was performed: Determination of plasma NT-proBNP levels by core laboratory (using reagents from Biomedica). (Using a test kit). Patient survival information was collected in week 52 of the trial.

[0053] Clinical trial product: Specifications: rhNRG-1, a 61-amino acid polypeptide, is an EGF of the neuregrin-1β2 isoform. It contains various domains and has a molecular weight of 7054 Dal (1 pg = 0.14 nmol). placebo: Specifications: Excipient for rhNRG-1 (250 pg / bag, does not contain activated recombinant human neuregulin-1 protein) Iaru). Medication regimen: [Table 1]

[0054] The criteria for participation in the clinical trial include a relatively stable clinical condition (clinical signs, symptoms, and more than one month). (Including approved standard treatments for CHF at target doses or maximum permissible doses) The study included patients with CHF (ages 18 to 65, NYHA class III or IV, LVEF ≤ 40%). Exclusion criteria include acute myocardial infarction, hypertrophic cardiomyopathy, constrictive pericarditis, significant valvular disease, or congenital disease. Heart disease, severe pulmonary hypertension, systolic blood pressure <90 mmHg or >160 mmHg, severe ventricular arrhythmia, This includes women who have undergone cardiac surgery, experienced a cerebrovascular event within the past six months, have claustrophobia, or are pregnant. All patients provided written consent.

[0055] (Embodiment 2: Recombinant human neuregulation in patients with chronic heart failure based on standard treatment) (Trial 301) A multicenter, randomized, double-blind, placebo-controlled survival trial. Evaluating the efficacy of recombinant human neuregulin (rhNRG-1) for injection in the treatment of chronic heart failure. To that end, a Phase III double-blind, multicenter, placebo-controlled, standard-of-care-based trial was conducted in multiple locations in China. The study was conducted at the clinical center. A total of 331 patients with NYHA class III or class IV chronic heart failure participated. Patients were enrolled and given either a placebo group, an rhNRG-1 group (0.6 μg / kg), or an rhNRG-1 group (1.0 μg / kg) to determine if they were unresponsive. The results were positive. There were no significant differences between the groups in terms of demographics or background treatment. The patient was hospitalized, administered medication as planned for 10 consecutive days, and discharged on the 11th day. From week 3 to week 25, the patient received weekly doses in the outpatient ward. Later, blood samples were taken from the patients. Core laboratory analysis of plasma NT-proBNP levels Decision made (using a reagent kit from Biomedica). Patient survival information was collected in week 52 of the trial. .

[0056] Clinical trial product: Specifications: rhNRG-1, a 61-amino acid polypeptide, is an EGF of the neuregrin-1β2 isoform. It contains various domains and has a molecular weight of 7054 Dal (1 pg = 0.14 nmol). placebo: Specifications: Excipient for rhNRG-1 (250 pg / bag, does not contain activated recombinant human neuregulin-1 protein) Iaru). Medication regimen: [Table 2]

[0057] The criteria for participation in the clinical trial include a relatively stable clinical condition (clinical signs, symptoms, and more than one month). (Including approved standard treatments for CHF at target doses or maximum permissible doses) This included patients aged 18 to 80 years with CHF (NYHA class III or IV) and LVEF ≤ 40%. The main exclusion criteria include acute myocardial infarction, hypertrophic cardiomyopathy, constrictive pericarditis, significant valvular disease, or congenital conditions. Cardiac heart disease, severe pulmonary hypertension, systolic blood pressure <90 mmHg or >160 mmHg, severe ventricular arrhythmia This includes women who have undergone cardiac surgery or a cerebrovascular event within the past six months, those with claustrophobia, or pregnant women. All patients provided written consent.

[0058] (Embodiment 3: Recombinant human neuregulation in patients with chronic heart failure based on standard treatment) (Trial 305) A multicenter, randomized, double-blind, placebo-controlled survival trial. Evaluating the efficacy of recombinant human neuregulin (rhNRG-1) for injection in the treatment of chronic heart failure. To that end, a double-blind, multicenter, placebo-controlled, standard-of-care-based trial was conducted by multiple clinical centers in China. The study was conducted at the center. A total of 679 patients with NYHA class II or class III chronic heart failure were included. Participants were enrolled and randomized to either the placebo group or the rhNRG-1 group (0.6 μg / kg). Demographic and biometric differences were observed between the groups. There was no significant difference in terms of ground treatment. Patients were hospitalized and treated as planned for 10 consecutive days. The patient was administered medication over several days and discharged on the 11th day. From week 3 to week 25, the patient was treated as an outpatient. The patient received a weekly dose in the ward. Blood samples were taken from the patient before treatment and after each dose. Determination of plasma NT-proBNP levels by core laboratory (using a reagent kit from Biomedica). (Using [the appropriate method]). Patient survival information was collected in week 52 of the trial.

[0059] Clinical trial product: Specifications: rhNRG-1, a 61-amino acid polypeptide, is an EGF of the neuregrin-1β2 isoform. It contains various domains and has a molecular weight of 7054 Dal (1 pg = 0.14 nmol). placebo: Specifications: Excipient for rhNRG-1 (250 pg / bag, does not contain activated recombinant human neuregulin-1 protein) Iaru). Medication regimen: [Table 3]

[0060] Clinical trial inclusion criteria: HF groups at target dose levels or maximum permissible doses for more than one month. Patients aged 18 and over who are receiving basic standard medical care and have stable clinical symptoms (including clinical symptoms and physical signs) A 75-year-old patient with chronic HF (NYHA functional class II or III) and LVEF ≤ 40%. Exclusion criteria: acute. Myocardial infarction, hypertrophic cardiomyopathy, stenotic pericarditis, significant valvular pathological changes or congenital heart disease, severe Severe pulmonary hypertension, systolic pressure <90 mmHg or >160 mmHg, severe ventricular arrhythmia, 6 months of testing Patients who have undergone cardiac surgery within the past month, or who have experienced cerebrovascular disease, or who are claustrophobic or pregnant. Pregnant women. All patients must understand and sign the informed consent form. There is a need.

[0061] The applicant conducted a statistical analysis of data obtained from three separate clinical trials. Three separate clinical trials in sex subjects (patients with mild, moderate, and severe NYHA class II-IV) Analysis of pooled data: Women in the treatment group compared to the treatment-based placebo-controlled group Compared to uncontrolled patients, the group achieved a statistically significant survival benefit (P=0.016). During the study period, the group was selected as a control group. The all-cause mortality rate decreased by more than 50%. In each separate trial, all women in the treatment group This achieved a survival benefit, consistent with trends observed from the analysis of pooled data from the three trials. This showed a trend.

[0062] Results obtained from the analysis of pooled data: Generally, during the trial period, the baseline N of the subjects The lower the T-proBNP level, the greater the survival benefit (relative reduction in all-cause mortality). Among women whose baseline NT-proBNP levels were ≤3000 fmol / mL, the treatment group The mortality rate in this group was 0%; in contrast, the mortality rate in the standard group of patients in the treatment-based placebo-controlled group was 0%. The causal mortality rate was approximately 10%; subjects in the treatment group achieved a statistically very significant survival benefit. (P<0.001). In all separate studies, the female population showed a tendency toward survival benefits, and pooled... This was consistent with the trends observed in the analysis of the collected data.

[0063] Clinical results suggest that rhNRG-1 is more effective in treating patients with mild to moderate heart failure. It has become clear that this can be determined, and this is because HF is induced by aortic coarctation. This aligns with research findings in rat models. The heart becomes curved, and blood pumping function is impaired. As HF progresses to a more severe stage, the expression of ErbB2 and ErbB4 receptors decreases significantly. This was shown. In light of this, the early stage of HF, i.e., ErbB2 / ErbB4 receptor expression Before downward adjustment, recombinant human neuregrin would provide greater benefits to patients. It is possible.

[0064] Table 1: Summary of all-cause mortality - subgroup analysis: (pooled analysis of data from trials 209 / 301 / 305) [Table 4] Abbreviations: LVEF = Left Ventricular Ejection Fraction, N = Total number of subjects analyzed, n = Number of subjects in a specific category, NY HA = New York Heart Association

[0065] The assay results revealed that the baseline NT-proBNP level was ≤1600 fmol / ml. In this case, rhNRG-1 showed the potential to significantly reduce mortality in subjects regardless of their sex. (Table 1); however, this conclusion is not valid for subjects with higher baseline NT-proBNP levels. This does not apply to the analysis of the pooled data. Further analysis shows that rhNRG-1 is all In the study involving women, it was found to result in a statistically significantly lower mortality rate. Table 1). As shown in Table 2, women showed the same trend in individual studies 209, 301 and 305. It was discovered.

[0066] Table 2: Summary of all-cause mortality - subgroup analysis: Single clinical trial (analysis of laboratory tests 209 / 301 / 305) [Table 5] Abbreviations: LVEF = Left Ventricular Ejection Fraction, N = Total number of subjects analyzed, n = Number of subjects in a specific category, NY HA = New York Heart Association

[0067] Women showed better improvement in both pooled and individual trials. Therefore, baseline NT-proBNP percentiles were used for further subgroup analysis in female subjects. These subgroups were classified as follows, as shown in Table 3: NT-proBNP ≤ 1600 fmol / ml (~50%), NT-proBNP Patients with a concentration of ≤3000 fmol / ml (~75%) and all female patients were subjected to pooled and single analyses. .

[0068] From a pooled analysis of three clinical trials 209, 301, and 305, the target group of women receiving rhNRG-1 treatment These are the three subgroups: the subgroup of patients receiving treatment with NT-proBNP ≤ 1600, and the subgroup of patients with NT-Pro BNP ≤ 3000 fmo. In the l / ml subgroup and in all female patients, the mortality rates for women were 0%, 0%, and 7.1%, respectively. This was revealed in three corresponding subgroups of subjects receiving a placebo. The mortality rates were 8.4%, 10.4%, and 16.1%, respectively; rhNRG-1 was particularly effective when NT-proBNP ≤ 3000 fm It was shown that the mortality rate could be significantly reduced in the ol / ml subgroup, as shown in Table 3. This subgroup of women accounted for 75% of the registered female population.

[0069] Individual analyses of trials 209, 301, and 305 showed that the NRG-1 treatment group in the trials was as shown in Table 3. In the NT-proBNP ≤ 3000 fmol / ml subgroup, the mortality rates for women were 0%, 0%, and 0%, respectively. The mortality rate was 0%, while the mortality rates in the corresponding placebo groups were 21.4%, 8.3%, and 6.3%, respectively. It became clear.

[0070] In male patients, in the NT-proBNP ≤ 4000 fmol / ml or NT-proBNP ≤ 3000 fmol / ml subgroups... Some clinical trials have shown that the mortality rate in the rhNRG-1 treatment group is better than in the placebo group. This was done. More preferably, in tests 209, 301 and 305, males with NT-proBNP ≤ 1600 fmol / ml Pooled analysis of the subjects showed that the mortality rate in the rhNRG-1 treatment group was significantly lower than in the placebo group. This was revealed (2.6% vs. 5.6%). This decrease was found in a comprehensive analysis of all subjects of both sexes. It followed.

[0071] Table 3: Summary of all-cause mortality analysis for the female subgroup: (pooled analysis of data from trials 209 / 301 / 305) (and individual analysis) [Table 6]

[0072] In light of the above analysis, women with NT-proBNP ≤ 3000 fmol / ml in any of the three clinical trials Individual and pooled analyses of the target population and male subjects with NT-proBNP ≤ 1600 fmol / ml are shown in Table 4. The study was conducted. Among these pooled male and female subjects, the mortality rate in the rhNRG-1 treatment group was investigated. The improvement in the failure rate was significantly better than in the placebo group.

[0073] Table 4: Summary of all-cause mortality - subgroup analysis: (pooled analysis of data from trials 209 / 301 / 305) (Individual analysis) [Table 7]

[0074] The above embodiments do not limit the scope of protection for the test. Those skilled in the art will understand the objectives of the present invention and The present invention can be adjusted and modified without departing from its scope. Therefore, the present invention The scope of protection should be defined according to the rights and requirements, not by specific embodiments.

Claims

1. A pharmaceutical composition for treating heart failure (HF) in a patient, wherein the pharmaceutical composition contains neuregulin (NRG), and the patient is a female HF patient whose pre-treatment plasma level of NT-proBNP is 3000 fmol / ml or less. The treatment includes an induction regimen and a maintenance regimen. The pharmaceutical composition is used in an introductory regimen in which NRG is administered to the patient at a dose of 0.6 μg / kg / day for 1 to 10 days. The pharmaceutical composition is used in a maintenance regimen in which NRG is administered to the patient once a week for 3 to 25 weeks at a dose of 0.8 μg / kg / day. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the NRG is NRG-1.

3. The pharmaceutical composition according to claim 1, wherein the NRG comprises the EGF-like domain of NRG-1.

4. The pharmaceutical composition according to claim 1, wherein the NRG comprises the amino acid sequence of Sequence ID No. 1.