Neuroregulatory proteins and uses thereof

Abstract

The invention also relates to the application of the neuregulin or the functional fragment thereof, or the nucleic acid for coding the neuregulin or the functional fragment thereof, or the substance for improving the yield and / or the function of the neuregulin in the human body in the medicine for preventing, treating or delaying the attack of the heart failure patient, and the medicine can improve the heart function of the heart failure patient and reverse the ventricular remodeling. Methods and devices for preventing, treating, or delaying the onset of heart failure patients are also provided.

Description

Neuregulin and its application Technical Field

[0001] The present invention relates to the field of medicine, and in particular to the use of neuregulin in the preparation of a drug for preventing, treating or delaying heart failure in humans, and a method for using neuregulin in the preparation of a drug for preventing, treating or delaying heart failure in humans. Background Art

[0002] Heart failure (HF) is a syndrome characterized by cardiac insufficiency resulting from various heart diseases. Current medications for HF primarily focus on angiotensin-converting enzyme (ACE) inhibitors, vasodilators that dilate blood vessels, lower blood pressure, and reduce cardiac workload. While the percentage reduction in mortality following the use of ACE inhibitors is statistically significant, the actual mortality rate only averages a 3%-4% reduction, and there are also potential side effects. Other options for preventing or treating HF also have corresponding limitations. For example, heart transplantation is significantly more expensive and invasive than drug therapy and is further limited by the availability of a donor heart. The use of mechanical devices, such as biventricular pacemakers, is also invasive and relatively expensive. Therefore, due to the inadequacy of current treatment options, new treatments are needed.

[0003] A promising new therapeutic approach involves administering neuregulin (NRG, neuregulin; HRG), also known as glial growth factor (GGF) and new differentiation factor (NDF), to patients with heart failure or at risk of heart failure. These glycoproteins, approximately 44 kDa, mediate intercellular signaling and are ligands for the ErbB family of tyrosine kinase receptors. The neuregulin family consists of four members: NRG1, NRG2, NRG3, and NRG4. NRGs are involved in a range of biological responses: stimulating breast cancer cell differentiation and milk protein secretion; inducing neural crest cell differentiation into Schwann cells; stimulating acetylcholine receptor synthesis in skeletal muscle cells; and promoting cardiomyocyte survival and DNA synthesis. In vivo studies using homozygous mouse embryos severely deficient in the neuregulin gene have demonstrated that neuregulin is essential for cardiac and neural development. NRG1 plays important roles in the nervous system, heart, and mammary glands. Evidence also suggests that NRG1 signaling plays a role in the development and function of several other organ systems, as well as in the pathogenesis of human diseases, including schizophrenia and breast cancer. NRG1 has numerous isoforms. Studies in mutant mice (knockout mice) have shown that isoforms that differ in the N-terminal region or in epidermal growth factor (EGF)-like regions have distinct in vivo functions.

[0004] Although various studies have been conducted on the functions of neuregulin, more research is needed on how to use neuregulin and how to achieve better therapeutic effects in certain subpopulations.

[0005] In addition, left ventricular (LV) function assessment is an important component of clinical decision-making in patients with heart disease. In particular, the left ventricular end-systolic volume index (LVESVI) is a measure of left ventricular function, and increased LVESVI is associated with an increased incidence of adverse events such as death or hospitalization. Currently, extremely high LVESVI values ​​(such as more than 135 mL / m 2 Patients with heart failure who have elevated LVESVI have a poor prognosis, and there are no specific reports on the treatment of such patients in the literature. The treatment of heart failure patients with particularly high LVESVI values ​​remains an unmet need and a major medical challenge.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a method for improving cardiac function in patients with heart failure using neuregulin, wherein the method uses a drug containing neuregulin in a special population suffering from chronic heart failure.

[0008] In a first aspect, the present invention provides the use of a neuregulin or a functional fragment thereof, or a nucleic acid encoding a neuregulin or a functional fragment thereof, or a substance that increases the production and / or function of a neuregulin in the human body, in the preparation of a drug for preventing, treating or delaying the onset of heart failure in patients, wherein the drug can improve the cardiac function of patients with heart failure.

[0009] The present invention provides use of neuregulin in preparing a drug for preventing and treating heart failure patients, delaying the onset of heart failure patients, or improving the cardiac function of heart failure patients.

[0010] In some embodiments, the heart failure patient has severe heart failure as assessed by a left ventricular function marker. In some embodiments, for example, the LVESVI value of a patient with severe heart failure is at least 3 times the LVESVI value of a healthy individual. In some embodiments, for example, the LVESVI value of a patient with severe heart failure is at least 4 times the LVESVI value of a healthy individual. In some embodiments, for example, the LVESVI value of a patient with severe heart failure exceeds the LVESVI value of a healthy individual by 100 mL / m 2In some embodiments, for example, a patient with severe heart failure has an LVESVI value that is in the top 40% of all heart failure patients. In some embodiments, for example, a patient with severe heart failure has an LVESVI value that is greater than or equal to about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL / m 2 In some embodiments, for example, patients with severe heart failure have an LVESVI value greater than or equal to about 135 mL / m 2 In some embodiments, the patients with severe heart failure are those with severe ventricular remodeling. In some embodiments, the patients with severe heart failure are those with enlarged hearts.

[0011] In some embodiments, for example, the present invention is used to prevent, treat, or delay LVESVI greater than or equal to about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL / m 2 In some embodiments, for example, a heart failure patient has a blood pressure of not less than about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL / m 2 LVESVI value.

[0012] In some embodiments, the heart failure patient is a patient with severe ventricular remodeling.

[0013] In some embodiments, the heart failure patient has a baseline LVESVI of ≥100 mL / m 2 , or ≥110 mL / m 2 , or ≥120 mL / m 2 , or ≥130 mL / m 2 , or ≥135 mL / m 2 , or ≥140 mL / m 2 , or ≥145 mL / m 2 , or ≥150 mL / m 2 , or ≥155 mL / m 2 , or ≥160 mL / m 2 , or ≥165 mL / m 2 , or ≥170 mL / m 2 ; preferably ≥135mL / m 2 ;

[0014] Alternatively, the heart failure patient has a baseline LVESVI of 100-350 mL / m 2 ; 110-350mL / m 2 120-350mL / m 2 ; 130-350mL / m 2 ; 135-350mL / m 2 ; preferably 135-350mL / m 2 .

[0015] In a preferred embodiment, the heart failure patient is a chronic heart failure patient.

[0016] In a preferred embodiment, the heart failure patient has a New York Heart Association (NYHA) heart function classification of NYHA II or III, or the plasma NT-proBNP level is no more than 4000 pg / ml.

[0017] In a preferred embodiment, among the heart failure patients, the plasma NT-proBNP level of male patients does not exceed 1700 pg / ml; the plasma NT-proBNP level of female patients does not exceed 4000 pg / ml.

[0018] In a preferred embodiment, the improving cardiac function of heart failure patients refers to improving LVESVI and / or LVEDVI.

[0019] In a specific embodiment, the LVESVI of the heart failure patient is reduced by equal to or greater than 10 mL / m 2 ; preferably equal to or greater than 20mL / m 2 .

[0020] In a specific embodiment, the LVEDVI of the heart failure patient is reduced by equal to or greater than 10 mL / m 2 ; preferably equal to or greater than 20mL / m 2 .

[0021] In a specific embodiment, the improving cardiac function of a heart failure patient is to simultaneously improve LVESVI and LVEDVI of a single heart failure patient.

[0022] In a specific embodiment, the single heart failure patient's LVESVI and LVEDVI are simultaneously reduced by equal to or greater than 20 or 25 mL / m 2 .

[0023] In certain embodiments, the heart failure patient undergoes reverse ventricular remodeling.

[0024] In a preferred embodiment, the improvement of LVESVI and / or LVEDVI is achieved when neuregulin is administered for 10 days.

[0025] In some embodiments, the neuregulin comprises neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).

[0026] In some embodiments, the neuregulin comprises neuregulin 1 (NRG-1).

[0027] In some embodiments, the neuregulin comprises an EGF-like region of neuregulin 1 (NRG-1).

[0028] In some embodiments, the neuregulin is a protein with an amino acid sequence as shown in SEQ ID NO: 1.

[0029] In a second aspect, the present invention provides a method for preventing, treating or delaying the onset of heart failure in patients, comprising administering to a patient in need an effective amount of a neuregulin or a functional fragment thereof, or a nucleic acid encoding a neuregulin or a functional fragment thereof, or a substance that increases the production and / or function of a neuregulin, wherein the method can improve the cardiac function of patients with heart failure.

[0030] The present invention provides a method for preventing and treating heart failure patients, delaying the onset of heart failure patients or improving the cardiac function of heart failure patients, comprising administering an effective amount of neuregulin to a patient in need.

[0031] In some embodiments, the heart failure patient has severe heart failure as assessed by a left ventricular function marker. In some embodiments, for example, the LVESVI value of a patient with severe heart failure is at least 3 times the LVESVI value of a healthy individual. In some embodiments, for example, the LVESVI value of a patient with severe heart failure is at least 4 times the LVESVI value of a healthy individual. In some embodiments, for example, the LVESVI value of a patient with severe heart failure exceeds the LVESVI value of a healthy individual by 100 mL / m 2 In some embodiments, for example, a patient with severe heart failure has a LVESVI value that is in the top 40% of all heart failure patients. In some embodiments, for example, a patient with severe heart failure has a LVESVI value that is greater than or equal to about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL / m 2 In some embodiments, for example, patients with severe heart failure have an LVESVI value greater than or equal to about 135 mL / m 2In some embodiments, the patients with severe heart failure are those with severe ventricular remodeling. In some embodiments, the patients with severe heart failure are those with enlarged hearts.

[0032] In some embodiments, for example, the present invention is used to prevent, treat, or delay LVESVI greater than or equal to about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL / m 2 In some embodiments, for example, a heart failure patient has a blood pressure of not less than about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL / m 2 LVESVI value.

[0033] In some embodiments, the heart failure patient is a patient with severe ventricular remodeling.

[0034] In some embodiments, the heart failure patient has a baseline LVESVI of ≥100 mL / m 2 , or ≥110 mL / m 2 , or ≥120 mL / m 2 , or ≥130 mL / m 2 , or ≥135 mL / m 2 , or ≥140 mL / m 2 , or ≥145 mL / m 2 , or ≥150 mL / m 2 , or ≥155 mL / m 2 , or ≥160 mL / m 2 , or ≥165 mL / m 2 , or ≥170 mL / m 2 ; preferably ≥135mL / m 2 ;

[0035] Alternatively, the heart failure patient has a baseline LVESVI of 100-350 mL / m 2 ; 110-350mL / m 2 120-350mL / m 2 ; 130-350mL / m 2 ; 135-350mL / m 2 ; preferably 135-350mL / m 2 .

[0036] In a preferred embodiment, the heart failure patient is a chronic heart failure patient.

[0037] In a preferred embodiment, the heart failure patient has a New York Heart Association (NYHA) heart function classification of NYHA II or III, or the plasma NT-proBNP level is no more than 4000 pg / ml.

[0038] In a preferred embodiment, among the heart failure patients, the plasma NT-proBNP level of male patients does not exceed 1700 pg / ml; the plasma NT-proBNP level of female patients does not exceed 4000 pg / ml.

[0039] In a preferred embodiment, the improving cardiac function of heart failure patients refers to improving LVESVI and / or LVEDVI.

[0040] In a specific embodiment, the LVESVI of the heart failure patient is reduced by equal to or greater than 10 mL / m 2 ; preferably equal to or greater than 20mL / m 2 .

[0041] In a specific embodiment, the LVEDVI of the heart failure patient is reduced by equal to or greater than 10 mL / m 2 ; preferably equal to or greater than 30mL / m 2 .

[0042] In a specific embodiment, the improving cardiac function of a heart failure patient is to simultaneously improve LVESVI and LVEDVI of a single heart failure patient.

[0043] In a specific embodiment, the single heart failure patient's LVESVI and LVEDVI are simultaneously reduced by equal to or greater than 20 or 25 mL / m 2 .

[0044] In a specific embodiment, said heart failure patient undergoes reverse heart failure remodeling.

[0045] In a preferred embodiment, the improvement of LVESVI and / or LVEDVI is achieved when neuregulin is administered for 10 days.

[0046] In a preferred embodiment, the method comprises administering neuregulin to the patient via an induction course of therapy.

[0047] In a preferred embodiment, the lead-in dosing regimen comprises continuous administration of the pharmaceutical composition for at least 3, 5, 7 or 10 days.

[0048] In preferred embodiments, the method comprises administering maintenance therapy to the patient for at least 3, 6, or 12 months.

[0049] In a preferred embodiment, the maintenance course comprises administering the drug every 3, 5, 7 or 10 days.

[0050] In a preferred embodiment, the method further comprises the step of evaluating whether the patient is suitable for neuregulin therapy before administering the drug to the patient in need of preventing, treating or delaying heart failure.

[0051] In a preferred embodiment, the step of assessing whether the patient is suitable for neuregulin therapy comprises assessing the NYHA cardiac function classification of the heart failure patient.

[0052] In a preferred embodiment, patients with NYHA class II or NYHA class III heart function are suitable for neuregulin therapy.

[0053] In a preferred embodiment, the step of evaluating whether the patient is suitable for neuregulin therapy further comprises detecting plasma NT-proBNP in patients with heart failure.

[0054] In a preferred embodiment, the plasma NT-proBNP level does not exceed 4000 pg / ml.

[0055] In a preferred embodiment, the plasma NT-proBNP level of the male heart failure patient does not exceed 1700 pg / ml; the plasma NT-proBNP level of the female heart failure patient does not exceed 4000 pg / ml.

[0056] In some embodiments, the neuregulin comprises neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).

[0057] In some embodiments, the neuregulin comprises neuregulin 1 (NRG-1).

[0058] In some embodiments, the neuregulin comprises an EGF-like region of neuregulin 1 (NRG-1).

[0059] In some embodiments, the neuregulin is a protein with an amino acid sequence as shown in SEQ ID NO: 1.

[0060] In a third aspect, the present invention provides a device for preventing, treating, or delaying the onset of heart failure in patients with heart failure, wherein the device is a device for improving LVESVI and / or LVEDVI in patients with heart failure, and the device comprises:

[0061] The treatment module is based on whether the patient's NYHA cardiac function classification is NYHA class II or NYHA class III, or whether the patient's plasma NT-proBNP is no more than 4000 pg / ml, or whether the patient's LVESVI in the baseline period before administration is ≥135 mL / m 2 Neuregulin therapy is administered to patients who are candidates for neuregulin therapy.

[0062] In a preferred embodiment, the device further comprises:

[0063] A detection module, which performs NYHA cardiac function classification on the patient, or detects the plasma NT-proBNP level of the heart failure patient, or detects the LVESVI value of the patient at baseline before drug administration; and

[0064] An analysis and judgment module, which analyzes and judges whether the patient's NYHA cardiac function rating is NYHA class II or NYHA class III, or whether the patient's plasma NT-proBNP is no more than 4000 pg / ml, or whether the patient's baseline LVESVI before administration is ≥135 mL / m 2 .

[0065] In a preferred embodiment, the plasma NT-proBNP level of the male heart failure patient does not exceed 1700 pg / ml; the plasma NT-proBNP level of the female heart failure patient does not exceed 4000 pg / ml.

[0066] In a preferred embodiment, the neuregulin is a protein having an amino acid sequence as shown in SEQ ID NO: 1.

[0067] In a preferred embodiment, the heart failure patients are those with severe ventricular remodeling.

[0068] In a preferred embodiment, the heart failure patient is a chronic heart failure patient.

[0069] In a preferred embodiment, the improving LVESVI and / or LVEDVI of a heart failure patient refers to reducing LVESVI and / or LVEDVI.

[0070] In a preferred embodiment, the LVESVI of the heart failure patient is reduced by equal to or greater than 10 mL / m 2 ; preferably equal to or greater than 20mL / m 2 .

[0071] In a preferred embodiment, the LVEDVI of the heart failure patient is reduced by 10 mL / m 2 ; preferably equal to or greater than 20mL / m2 .

[0072] In a preferred embodiment, the baseline LVESVI of the heart failure patient before administration is ≥135 mL / m 2 .

[0073] In a preferred embodiment, the heart failure patient is a heart failure patient with improved LVESVI and LVEDVI at the same time.

[0074] In a preferred embodiment, the LVESVI and LVEDVI of the heart failure patient are simultaneously reduced by 20 or more or 25 mL / m 2 .

[0075] In a preferred embodiment, the heart failure patient undergoes reverse ventricular remodeling.

[0076] In a preferred embodiment, the improvement of LVESVI and / or LVEDVI is achieved when neuregulin is administered for 10 days.

[0077] In a preferred embodiment, the therapeutic module comprises a device for administering neuregulin to a patient via an infusion therapy regimen.

[0078] In preferred embodiments, the therapeutic module comprises means for continuous administration of neuregulin for at least 3, 5, 7, or 10 days.

[0079] In a preferred embodiment, the treatment module includes means for maintaining the patient for a course of at least 3, 6 or 12 months.

[0080] In a preferred embodiment, the maintenance course comprises administering the drug every 3, 5, 7 or 10 days.

[0081] In some embodiments, the neuregulin comprises neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).

[0082] In some embodiments, the neuregulin comprises neuregulin 1 (NRG-1).

[0083] In some embodiments, the neuregulin comprises an EGF-like region of neuregulin 1 (NRG-1).

[0084] In some embodiments, the neuregulin is a protein with an amino acid sequence as shown in SEQ ID NO: 1.

[0085] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 shows the proportion of patients with reduced and increased LVESVI at 30 days treated with neuregulin;

[0087] Figure 2 shows the difference in LVESVI improvement compared to baseline between the neuregulin and placebo groups at 30 days;

[0088] Figure 3 shows the difference in LVESVI worsening compared to baseline at day 30 between the neuregulin and placebo groups;

[0089] Figure 4 shows the improvement of the cardiac function index LVESVI compared with the baseline at 30 days and 90 days;

[0090] Figure 5 shows the difference in improvement in LVEDVI compared to baseline between the neuregulin and placebo groups at 30 days;

[0091] Figure 6 shows the difference in LVEDVI worsening compared to baseline between the neuregulin and placebo groups at 30 days;

[0092] FIG7 shows that at 30 days, both LVESVI and LVEDVI of the subjects were significantly improved.

[0093] Figure 8 shows the effect of neuregulin on the enriched subgroup (baseline LVESVI ≥ 135 mL / m 2 ) significantly improved (LVESVI decreased by 13 mL / m 2 Above) were significantly higher than those in the placebo group;

[0094] Figure 9 shows the effect of neuregulin on the enriched population (baseline LVESVI ≥ 135 mL / m 2 )'s LVESVI and LVEDVI were significantly improved (both indicators decreased by 20 mL / m 2 significantly higher than those in the placebo group.

[0095] Figure 10 shows the effect of neuregulin on the enriched population (baseline LVESVI ≥ 135 mL / m 2 )'s LVESVI and LVEDVI were significantly improved (both indicators decreased by 20 mL / m 2 The response rate of the patients was higher than that of the whole population.

[0096] Figure 11a shows the effect of neuregulin on the enriched population (baseline LVESVI ≥ 135 mL / m) 30 days after administration. 2 ) had a better mean improvement in LVESVI relative to baseline than the whole population.

[0097] Figure 11b shows the effect of neuregulin on the enriched population (baseline LVESVI ≥ 135 mL / m) 30 days after administration. 2 ) had a better mean improvement in LVEDVI relative to baseline than the whole population. DETAILED DESCRIPTION

[0098] The present invention includes that heart failure patients selected by New York Heart Association (NYHA) cardiac function classification and / or detecting NT-proBNP levels in patient plasma can achieve significant therapeutic effects after being treated with neuregulin.

[0099] The neuregulins described herein can improve cardiac function or prevent worsening of cardiac function in patients with heart failure, wherein the improvement in cardiac function includes a reduction in LVESVI and / or LVEDVI. In specific embodiments, both LVESVI and LVEDVI are significantly reduced in some individual subjects. In other embodiments, the higher the baseline LVESVI level in an individual subject, the greater the improvement in cardiac function.

[0100] Unless otherwise specified, all technical and scientific terms used herein are as commonly understood by those skilled in the art to which this invention belongs. All patents, patent applications, published patents, and other publications are incorporated herein by reference. In the event of any inconsistency or conflict between the definitions set forth in this section and those in the aforementioned references, the definitions set forth in this section shall prevail.

[0101] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include corresponding plural references and are used interchangeably with "at least one" or "one or more than one," unless the context clearly dictates otherwise.

[0102] The present invention is based on neuregulin 1β (NRG1β). Neuregulin 1β is a transmembrane protein. Its extracellular portion, comprising an immunoglobulin (Ig)-like domain and an EGF-like domain, is the N-terminus, while its intracellular portion is the C-terminus. Under the action of metalloproteinases in the extracellular matrix, the extracellular portion of neuregulin can be enzymatically cleaved, leaving it in a free state. This facilitates binding to ErbB receptors on the surface of surrounding cells, activating corresponding cellular signaling.

[0103] The ErbB receptor family is divided into four categories: ErbB1, ErbB2, ErbB3, and ErbB4. These are transmembrane proteins with molecular weights ranging from 180 to 185 kDa. With the exception of ErbB2, all contain ligand-binding domains at their N-termini, which are located outside the membrane; with the exception of ErbB3, all possess protein tyrosine kinase activity at their C-termini, which are located inside the membrane. ErbB1 is a receptor for epidermal growth factor, while ErbB3 and ErbB4 are receptors for neuregulin. Among these neuregulin receptors, only ErbB2 and ErbB4 are expressed at high levels in the heart.

[0104] When neuregulin binds to the extracellular portion of ErbB3 or ErbB4, it causes ErbB3, ErbB4, and other ErbB receptors (often including ErbB2) to form heterodimers, or ErbB4 itself to form homodimers, which then leads to phosphorylation of the intracellular portion of the receptor. The phosphorylated intracellular portion can further bind to various signaling proteins within the cell, thereby activating the downstream ERK or AKT signaling pathways, triggering a series of cellular responses, including stimulation or inhibition of cell proliferation, apoptosis, cell migration, cell differentiation, or cell adhesion.

[0105] Studies have shown that the EGF-like domain of NRG-1, approximately 50 to 64 amino acids, is sufficient to bind to and activate these receptors. Previous studies have shown that neuregulin-1β (NRG-1β) directly binds to ErbB3 and ErbB4 with high affinity. The orphan receptor ErbB2 can form heterodimers with ErbB3 or ErbB4 with higher affinity than with ErbB3 or ErbB4 homodimers. Neurodevelopmental research suggests that the development of the sympathetic nervous system requires an intact NRG-1β, ErbB2, and ErbB3 signaling system. Targeted disruption of NRG-1β, ErbB2, or ErbB4 results in embryonic lethality due to defects in cardiac development. Recent studies have also highlighted the important roles of NRG-1β, ErbB2, and ErbB4 in cardiovascular development and in maintaining normal adult cardiac function. Studies have shown that NRG-1β enhances the sarcomere organization of adult cardiomyocytes.

[0106] As used herein, "neuregulin" or "neuregulin" or "NRG" refers to a protein or polypeptide that can bind to and activate ErbB2, ErbB3, ErbB4, or heterodimers thereof, or homodimers thereof, including isoforms of neuregulin, EGF-like functional domains in neuregulin, polypeptides comprising EGF-like functional domains of neuregulin, mutants or derivatives of neuregulin, and other neuregulin-like gene products that can activate the above receptors. Neuregulin also includes NRG-1, NRG-2, NRG-3, and NRG-4 proteins, polypeptides, fragments, and complexes with NRG-like functions. Preferably, neuregulin is a protein or polypeptide that can bind to and activate ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimers. By way of example, but not for the purpose of limitation, the neuregulin of the present invention is a fragment of the NRG-1β2 isoform, i.e., a fragment of amino acids 177-237, which comprises an EGF-like functional domain. The amino acid sequence of this fragment is: SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVMASFYKAEELYQ (SEQ ID NO: 1). The neuregulin used in the present invention can activate the above-mentioned receptors and regulate their biological functions, such as stimulating skeletal muscle cells to synthesize acetylcholine receptors; promoting the differentiation, survival and DNA synthesis of cardiomyocytes. Neuregulin also includes neuregulin mutants with conservative mutations that do not substantially affect biological functions, such as mutations of single amino acids in non-critical regions (see Watson et al., Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin / Cummings Pub.co., p. 224). The neuregulin used in the present invention can be isolated from natural sources, or obtained by recombinant technology, artificial synthesis or other means.

[0107] As used herein, the "epidermal growth factor-like domain" or "EGF-like region" or "EGF-like domain" refers to a polypeptide fragment encoded by the neuregulin gene that can bind to and activate ErbB2, ErbB3, ErbB4 or their heterologous or homologous dimers, and has structural similarity to the EGF receptor binding region described in the following references: WO 00 / 64400; Holmes et al., Science, 256:1205-1210 (1992); U.S. Patents 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. In certain embodiments, the EGF-like domain binds to and activates ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimers. In certain embodiments, the EGF-like domain comprises amino acids from the receptor binding region of NRG-1. In certain embodiments, the EGF-like domain refers to amino acids 177-226, 177-237, or 177-240 of NRG-1. In certain embodiments, the EGF-like domain comprises amino acids from the receptor binding region of NRG-2. In certain embodiments, the EGF-like domain comprises amino acids from the receptor binding region of NRG-3. In certain embodiments, the EGF-like domain comprises amino acids from the receptor binding region of NRG-4. In certain embodiments, the EGF-like domain comprises the amino acid sequence described in U.S. Patent No. 5,834,229: Ala Glu Lys Glu Lys Thr Phe Cys Val Asn Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro (SEQ ID NO: 2).

[0108] As used herein, "treatment" refers to any means by which the symptoms of a discomfort, disorder, or disease are ameliorated or altered for the better. The effect can be prophylactic, completely or partially preventing the onset of a disease or its symptoms, or therapeutic, partially or completely curing a disease and / or its adverse effects. Treatment also includes any pharmaceutical use of the compositions described herein.

[0109] As used herein, "heart failure" or "heart failure" refers to an abnormality in cardiac function in which the heart is unable to pump blood as needed for tissue metabolism. Heart failure includes a variety of disease states such as congestive heart failure, myocardial infarction, arrhythmias, familial hypertrophic cardiomyopathy, ischemic heart disease, idiopathic cardiomyopathy, and myocarditis. Heart failure can be caused by a variety of factors, including but not limited to ischemic, congenital, rheumatic, viral, toxic, or idiopathic heart failure. Chronic cardiac hypertrophy is a significant pre-congestive heart failure disease state that can lead to cardiac arrest.

[0110] Unless otherwise indicated in the context, the terms "protein", "polypeptide" and "peptide" used herein have the same meaning.

[0111] As used herein, "not more than" means "less than or equal to" unless the context indicates otherwise.

[0112] Unless otherwise indicated, "about" or "approximately" for a value herein means within 10% of the value.

[0113] As used herein, "LVESVI" refers to left ventricular end-systolic volume index. As used herein, "LVEDVI" refers to left ventricular end-diastolic volume index.

[0114] The left ventricular end-systolic volume index (LVESVI) is the volume of the left ventricle at its smallest contraction divided by body surface area, making the assessment of left ventricular end-systolic volume unaffected by factors such as height and weight. LVESVI can be measured by two-dimensional (2D ECHO) and three-dimensional (3D ECHO) echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging (CMR). In healthy individuals, female LVESVI is usually between 8 and 27 mL / m 2 In the range, men usually have a range of 9 to 31 mL / m 2 within the range.

[0115] Left ventricular end-diastolic volume index (LVEDVI) is the volume of the left ventricle at end-diastole divided by body surface area. LVEDVI can be measured by two-dimensional (2D ECHO) and three-dimensional (3D ECHO) echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging (CMR). In healthy individuals, LVEDVI in women is typically between 29 and 70 mL / m 2 In the range, men usually have a range of 30 to 79 mL / m 2 within the range.

[0116] Cardiac systolic function is related to factors such as preload, afterload, contractility, and myocardial mass. LVESVI is a systolic function and prognostic indicator. A simultaneous decrease in both LVEDVI and LVESVI in the same individual is clear and unequivocal evidence of enhanced myocardial contractility, improved cardiac function, and reversed ventricular remodeling, effectively reducing mortality in heart failure patients.

[0117] As used herein, "N-terminal pro-brain natriuretic peptide" or "NT-proBNP" refers to the inactive pro-BNP fragment. Pro-BNP is the precursor of BNP, a hormone-related active natriuretic peptide primarily released by cardiomyocytes lining the left ventricular wall. In response to the contraction and expansion of the myocardial wall, pro-BNP undergoes proteolytic cleavage, splitting it into BNP and the inactive NT-proBNP.

[0118] Plasma levels of BNP and NT-proBNP are useful for screening and diagnosing heart failure, and for establishing a prognosis for heart failure, as both markers are typically elevated in patients whose disease worsens. Furthermore, the methods of the present invention include using BNP or NT-proBNP levels to identify patients suitable for treatment of heart failure with neuregulin.

[0119] The "New York Heart Association" or "NYHA" cardiac functional classification used in this article is a method for classifying the degree of heart failure. It divides patients into four categories based on the degree of limitation of their physical activity. Limitations or symptoms refer to normal breathing and varying degrees of dyspnea and / or angina: I, asymptomatic and normal activity is not limited, such as dyspnea when walking, climbing stairs, etc.; II, mild symptoms (mild dyspnea and / or angina) and normal activity is slightly limited; III, physical activity is significantly limited, even in the case of less than normal activity, for example, short distance walking (20-100m), feeling comfortable at rest; IV, severely limited activity, symptoms are present even at rest, and most patients are bedridden.

[0120] Advantages of the present invention:

[0121] The neuregulin of the present invention can improve the cardiac function of patients with heart failure, especially improve the LVESVI and LVEDVI of a single heart failure patient at the same time; at the same time, the present invention surprisingly found that the neuregulin is effective for patients with heart failure who have a high baseline LVESVI value, especially those with LVESVI ≥ 135 mL / m 2 The unexpected improvement in cardiac function in patients with heart failure was better than the improvement in cardiac function in all patients with heart failure.

[0122] The effect of the neuregulin of the present invention on improving cardiac function in patients with heart failure can be maintained for a long time, for example, up to 90 days after administration;

[0123] The neuregulin of the present invention directly acts on myocardial cells, repairs their damaged structure and function, enhances myocardial contractility, and reverses ventricular remodeling.

[0124] The present invention will be further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally carried out under conventional conditions, such as those described in textbooks, or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0125] Example 1: A multicenter, randomized, double-blind, placebo-controlled phase III clinical trial based on standard treatment to evaluate the effects of recombinant human neuregulin for injection on cardiac function in subjects with chronic systolic heart failure.

[0126] The trial in this example used a multicenter, randomized, double-blind, placebo-controlled parallel study based on standard treatment to evaluate the effects of recombinant human neuranglin for injection on cardiac function in patients with chronic systolic heart failure (New York Heart Association class II-III) with NT-proBNP ≤ 1700 pg / ml in males and NTproBNP ≤ 4000 pg / ml in females, to confirm its efficacy and safety.

[0127] 1. Experimental Design

[0128] A multicenter, randomized, double-blind, placebo-controlled parallel study based on standard treatment

[0129] Experimental group: recombinant human neuregulin for injection + standard basic treatment drugs (β-blockers, ACEI / ARB / ARNI, aldosterone receptor antagonists, etc.).

[0130] Placebo group: placebo + standard basic treatment drugs (β-blockers, ACEI / ARB / ARNI, aldosterone receptor antagonists, etc.).

[0131] 2. Main inclusion criteria

[0132] 2.1 Aged 18-75, gender not limited;

[0133] 2.2 Patients with a confirmed diagnosis of heart failure for 3 months or more, currently in stable condition, NYHA class II-III, and left ventricular ejection fraction (LVEF) ≤40%;

[0134] 2.3 NT-proBNP ≤ 1700 pg / ml for men and ≤ 4000 pg / ml for women;

[0135] 2.4 Patients have received standard basic treatment drugs for heart failure for at least 3 months and have reached the target dose or maximum tolerated dose for more than 1 month, or the dose has not been changed within 1 month;

[0136] 2.5 Understand and sign the informed consent form.

[0137] 3. Experimental drugs:

[0138] 3.1 Test Drugs

[0139] Name: Recombinant human neuregulin for injection

[0140] Specifications: Neucardin, 61 amino acids constituting the EGF-like functional domain of the Neuregulin-1β2 isomer, with a molecular weight of 7054 Da1 (1 μg = 0.14 nmol); 250 μg / vial.

[0141] Dosage form: Powder injection

[0142] Route of administration: intravenous drip

[0143] Appearance: freeze-dried block or powder

[0144] 3.2 Placebo

[0145] Name: Excipients for recombinant human neuregulin lyophilized preparation for injection

[0146] Specifications: Neucardin excipients (250 μg / vial, does not contain the active ingredient of recombinant human neucardin protein)

[0147] Dosage form: Powder injection

[0148] Route of administration: intravenous drip

[0149] Appearance: freeze-dried block or powder

[0150] Color: white or off-white

[0151] 4. The route of administration, dosage and course of treatment are shown in Table 1:

[0152] Table 1. Route of administration, dosage and course of treatment

[0153] 5. Data collection: Efficacy and safety assessments will be conducted during the screening period, 30 days after administration, and 90 days after administration.

[0154] 6. Results:

[0155] This example was conducted simultaneously in multiple clinical research centers across China. A total of 154 patients were enrolled, including 78 patients in the neuregulin trial group and 76 patients in the placebo group. Ultimately, a total of 147 patients (73 patients in the trial group and 74 patients in the placebo group) achieved the primary endpoint.

[0156] 6.1 LVESVI

[0157] According to the 30-day data obtained, 63% of patients in the Neuregulin experimental group had a reduction in LVESVI (see Figure 1), and the proportion of patients with a 30-day reduction in LVESVI compared to baseline was also higher than that in the placebo group.

[0158] The improvement value of LVESVI compared with baseline at 30 days after administration was stratified (greater than or equal to 5, 10, 15, 20, 25, 30, 35, 40 ml / m 2 ), and the improvement rates of each level in the neuregulin group and the placebo group were calculated. LVESVI decreased by 5, 10, 15, 20, 25, 30, 35, and 40 ml / m compared with the baseline. 2 The corresponding improvement rates in the Neuregulin group were 45.2%, 34.2%, 23.3%, 17.8%, 15.1%, 8.2%, 5.5%, and 2.7%, respectively; and the corresponding improvement rates in the placebo group were 52.7%, 31.1%, 16.2%, 5.4%, 2.7%, 2.7%, 2.7%, and 2.7%, respectively. Relative to the placebo group, as the degree of improvement increased, the proportion of improved patients in the Neuregulin group showed a significant difference from that in the placebo group, indicating that Neuregulin was more effective than placebo in improving LVESVI. When LVESVI improved by 20 and 25 ml / m 2 There was a statistically significant difference in the improvement rate between the two groups (P<0.05, see Figure 2).

[0159] In addition, by analyzing the two CMR test results of the subjects in the stable period within 1 month before enrollment, under the existing standard treatment conditions, without the intervention of the trial drug, the LVESVI decreased by more than 25ml / m within 1 month. 2 The natural occurrence rate of patients with the above symptoms was 2.58%, which was higher than that of the placebo group who improved by more than 25 ml / m within 1 month after taking the medicine. 2 The proportion was close to (2.7%), indicating that LVESVI improved by more than 25 ml / m within one month. 2 The improvement rate data for the neuregulin group was stable, and the 15.1% improvement rate achieved within one month was significantly higher than the naturally occurring rate. In summary, this indicates that the drug significantly increased the rate of significant improvement in cardiac function in the subjects.

[0160] Analysis of the differences in cardiac function deterioration between the Neuregulin trial group and the placebo group at 30 days showed (see Table 2 and Figure 3) that the proportion of subjects with increased LVESVI in the Neuregulin trial group was lower than that in the placebo group, which was consistent with the trend of improved cardiac function with reduced LVESVI, indicating that Neuregulin can prevent the deterioration of cardiac function in subjects.

[0161] Table 2. LVESVI Increases of ≥5, 10, 15, 20, 25, and 30 ml / m2 from Baseline at 30 Days 2 (FAS)

[0162] Note: N = number of subjects in the group who obtained LVESVI indicators; n = number of subjects in a specific category

[0163] Cardiac function was measured 30 days after administration in the Neuregulin group, and LVESVI improved by 5.62 ml / m 2 The improvement was statistically significant (P=0.0137), and the improvement effect could be maintained until the 90-day measurement (P=0.0128); while the placebo group did not show statistically significant differences in cardiac function at 30 and 90 days after medication compared with before medication (P greater than 0.05) (see Table 3 and Figure 4).

[0164] Table 3. ΔLVESVI at 30 and 90 days

[0165] 6.2 LVEDVI

[0166] The 30-day LVEDVI data showed that the proportion of patients who achieved a 30-day LVEDVI reduction from baseline was higher in the neuregulin group than in the placebo group. For 30-day LVEDVI reductions of 5, 10, 15, 20, 25, 30, 35, and 40 ml / m², the corresponding improvement rates in the neuregulin group were 43.8%, 30.1%, 21.9%, 17.8%, 16.4%, 13.7%, 6.8%, and 5.5%, respectively, compared to 44.6%, 29.7%, 14.9%, 12.2%, 6.8%, 4.1%, 4.1%, and 2.7%, respectively, in the placebo group.

[0167] Especially if LVEDVI decreases by 30 ml / m or more 2 At the time of the study, the neuregulin trial group consisted of 10 participants, with an improvement rate of 13.7%, while the placebo group consisted of 3 participants, with an improvement rate of 4.1%. The p-value was 0.046 (see Table 4 and Figure 5). The proportion of participants in the neuregulin trial group was significantly higher than that in the placebo group, and the difference was statistically significant. This indicates that the drug significantly increased the rate of substantial improvement in cardiac function in the participants.

[0168] Table 4. LVEDVI reductions greater than or equal to 5, 10, 15, 20, 25, 30, 35, and 40 ml / m2 at 30 days compared with baseline. 2 (FAS)

[0169] Note: N = number of subjects in the group who obtained LVESVI indicators; n = number of subjects in a specific category

[0170] The analysis of the differences in cardiac function deterioration at 30 days between the Neuregulin trial group and the placebo group showed (see Table 5 and Figure 6) that the proportion of subjects with increased LVEDVI in the Neuregulin trial group was lower than that in the placebo group, which is consistent with the above analysis of the improvement of cardiac function by reducing LVEDVI, indicating that Neuregulin can prevent the deterioration of cardiac function in subjects.

[0171] Table 5. 30-day increase in LVEDVI from baseline greater than or equal to 5, 10, 15, 20, 25, and 30 ml / m 2 (FAS)

[0172] Note: N = number of subjects in the group who obtained LVESVI indicators; n = number of subjects in a specific category

[0173] 6.3 LVESVI and LVEDVI

[0174] According to the data of LVESVI and LVEDVI of individual subjects, LVESVI and LVEDVI of individual subjects decreased by 5, 10, 15, 20, 25, 30, 35, and 40 ml / m3 respectively compared with the baseline 30 days after administration. 2 The corresponding improvement rates in the neuregulin group were 37.0%, 23.3%, 19.2%, 16.4%, 12.3%, 6.8%, 4.1%, and 1.4%, respectively; and in the placebo group were 39.2%, 20.3%, 12.2%, 2.7%, 2.7%, 2.7%, 2.7%, and 1.4%, respectively. Individual LVESV and LVEDV improved simultaneously in the subjects, with a particular decrease of 20 ml / m2 in both LVESVI and LVEDV. 2 At the same time, there were 12 patients in the neuregulin trial group with an improvement rate of 16.4%, and 2 patients in the placebo group with an improvement rate of 2.7%. The p value was 0.0048 (see Table 6 and Figure 7). The difference was statistically significant, indicating that neuregulin can improve cardiac function and significantly reverse ventricular remodeling.

[0175] Table 6. Simultaneous reductions of LVESVI and LVEDVI from baseline by 5, 10, 15, 20, 25, 30, 35, and 40 ml / m2 for a single individual at 30 days. 2 (FAS)

[0176] Note: N = number of subjects in the group who obtained LVESVI indicators; n = number of subjects in a specific category

[0177] The analysis of the differences in cardiac function deterioration between the Neuregulin trial group and the placebo group at 30 days showed (see Table 7) that the proportion of individuals in the Neuregulin trial group with simultaneous increases in LVESVI and LVEDVI was lower than that in the placebo group, which is consistent with the above analysis of the improvement of cardiac function by simultaneous decreases in LVESVI and LVEDVI, indicating that Neuregulin can prevent the deterioration of cardiac function in subjects.

[0178] Table 7. LVESVI and LVEDVI increased by 5, 10, 15, 20, 25, and 30 ml / m2 over baseline at 30 days. 2 (FAS)

[0179] Note: N = number of subjects in the group who obtained LVESVI indicators; n = number of subjects in a specific category

[0180] Example 2. Study on the effect of improving cardiac function in enriched subgroups-1

[0181] By statistically analyzing the experimental results of Example 1, the present inventors studied the effect of neuregulin on improving LVESVI (more than 13 mL / m 2 The enriched population here refers to those with baseline LVESVI ≥ 135 mL / m 2 Patients with HFrEF, accounting for approximately 41% of the total population, generally suffer from severe heart failure and severe ventricular remodeling.

[0182] The results unexpectedly found that (as shown in Figure 8) neuregulin had a significant effect on the enriched subgroup of the population (baseline LVESVI ≥ 135 mL / m 2 , accounting for about 41% of the subject population) had a better effect on improving cardiac function.

[0183] The LVESVI of the enriched subgroup of patients treated with Neuregulin was significantly improved (LVESVI decreased by 13 mL / m 2 The response rate of the 2-week treatment group was 50%, which was significantly higher than that of the placebo group.

[0184] The above results indicate that a larger baseline LVESVI indicates a larger heart, and that neuregulin has a better therapeutic effect on a larger heart.

[0185] Example 3. Study on the effect of improving cardiac function in enriched subgroup population-2

[0186] By statistically analyzing the experimental results of Example 1, the present inventors studied the effect of neuregulin on the improvement of LVESVI and LVEDVI in enriched patients (both exceeding 20 mL / m 2 ) response rate.

[0187] The results unexpectedly found that (as shown in Figure 9): the enriched population (baseline LVESVI ≥ 135 mL / m 2 ) In the Newcardin group, patients experienced significant improvement in LVESVI and LVEDVI (both indicators decreased by 20 mL / m 2 The response rate of the 24-hour follow-up group was significantly higher than that of the placebo group.

[0188] At the same time, by comparing the whole population and the enriched population (baseline LVESVI ≥ 135 mL / m 2 ) in the Newcardin group and the placebo group, the LVESVI and LVEDVI of the patients were significantly improved (both indicators decreased by 20 mL / m 2 The present invention surprisingly found that although the significant improvement in LVESVI and LVEDVI in the individual patients in the neukadine group in both the whole population and the enriched population was significantly higher than that in the placebo group, the neukadine group in the enriched population had a significant improvement in LVESVI and LVEDVI compared to the neukadine group in the whole population (both indicators were reduced by 20 mL / m 2 As shown in Figure 10.

[0189] The present invention further calculated the mean improvement in LVESVI or LVEDVI relative to baseline 30 days after administration of Neucardin or placebo in the entire population and enriched population. Similarly, it was surprisingly found that although the mean improvement in LVESVI or LVEDVI relative to baseline in the Neucardin-treated group was better than that in the placebo group in both the entire population and the enriched population, the Neucardin-treated group in the enriched population had a greater mean improvement in LVESVI or LVEDVI relative to baseline than the Neucardin-treated group in the entire population, as shown in Figures 11a and 11b. These results suggest that Neucardin is more effective in improving cardiac function in this enriched population, and therefore more effective in preventing, treating, or delaying the onset of heart failure in this enriched population.

[0190] Therefore, neuregulin is effective in enriched population (baseline LVESVI ≥ 135 mL / m 2 ) has better efficacy: LVESVI in the treatment group improved by more than 13 mL / m 2 The response rate reached 50%, which was statistically significant; the individual LVESVI and LVEDVI of the subjects improved by more than 20 mL / m 2The response rate was 26.5% (0% for placebo, which was statistically significant).

[0191] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. Use of a neuregulin or a functional fragment thereof, or a nucleic acid encoding a neuregulin or a functional fragment thereof, or a substance that increases the production and / or function of a neuregulin in the human body, in the preparation of a drug for preventing, treating, or delaying the onset of heart failure in patients with heart failure, wherein the drug can improve cardiac function in patients with heart failure.

2. Use of neuregulin in the preparation of drugs for preventing and treating heart failure, delaying the onset of heart failure, or improving cardiac function in heart failure patients.

3. The use according to claim 1 or 2, characterized in that The heart failure patients are those with severe ventricular remodeling.

4. The use according to any one of claims 1 to 3, characterized in that The heart failure patients had a baseline LVESVI of ≥100 mL / m 2 , or ≥110 mL / m 2 , or ≥120 mL / m 2 , or ≥130 mL / m 2 , or ≥135 mL / m 2 , or ≥140 mL / m 2 , or ≥145 mL / m 2 , or ≥150 mL / m 2 , or ≥155 mL / m 2 , or ≥160 mL / m 2 , or ≥165 mL / m 2 , or ≥170 mL / m 2 ; preferably ≥135mL / m 2 ; Alternatively, the heart failure patient has a baseline LVESVI of 100-350 mL / m 2 ; 110-350mL / m 2 120-350mL / m 2 ; 130-350mL / m 2 ; 135-350mL / m 2 ; preferably 135-350mL / m 2 .

5. The use according to any one of claims 1 to 4, characterized in that The heart failure patient is a chronic heart failure patient.

6. The use according to any one of claims 1 to 5, characterized in that The heart failure patients were classified as New York Heart Association (NYHA) II or III heart function classification.

7. The use according to any one of claims 1 to 6, characterized in that The NT-proBNP level in the plasma of the heart failure patient does not exceed 4000 pg / ml.

8. The use according to any one of claims 1 to 7, characterized in that Among the heart failure patients, the plasma NT-proBNP level of male patients does not exceed 1700 pg / ml; the plasma NT-proBNP level of female patients does not exceed 4000 pg / ml.

9. The method according to any one of claims 1 to 8, wherein Improving the cardiac function of patients with heart failure refers to improving LVESVI and / or LVEDVI.

10. The use according to any one of claims 1 to 9, characterized in that The heart failure patient's LVESVI decreased by equal to or greater than 10 mL / m after administration. 2 ; preferably equal to or greater than 20mL / m 2 .

11. The use according to any one of claims 1 to 10, characterized in that The heart failure patients Decreased LVEDVI equal to or greater than 10 mL / m 2 ; preferably equal to or greater than 20mL / m 2 .

12. The use according to any one of claims 1 to 11, characterized in that The improving the cardiac function of a heart failure patient is to simultaneously improve the LVESVI and LVEDVI of a single heart failure patient.

13. The use according to claim 12, characterized in that The single heart failure patient simultaneously decreases LVESVI and LVEDVI by 20 or more or 25 mL / m after administration. 2 .

14. The use according to any one of claims 1 to 13, characterized in that The drug reverses ventricular remodeling in patients with heart failure.

15. The use according to any one of claims 1 to 14, characterized in that The neuregulins include neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).

16. The use according to any one of claims 1 to 14, characterized in that The neuregulin comprises neuregulin 1 (NRG-1) or an EGF-like region of NRG-1.

17. The use according to any one of claims 1 to 14, characterized in that The neuregulin is a protein with an amino acid sequence as shown in SEQ ID NO:

1.

18. A method for preventing, treating or delaying the onset of heart failure in patients, comprising administering to a patient in need thereof an effective amount of a neuregulin or a functional fragment thereof, or a nucleic acid encoding a neuregulin or a functional fragment thereof, or a substance that increases the production and / or function of a neuregulin, wherein the method can improve cardiac function in patients with heart failure.

19. A method for preventing, treating, delaying the onset of heart failure, or improving cardiac function in patients with heart failure, comprising administering an effective amount of neuregulin to a patient in need thereof.

20. The use according to claim 18 or 19, characterized in that The heart failure patients are those with severe ventricular remodeling.

21. The method according to any one of claims 18 to 20, wherein: The heart failure patients had a baseline LVESVI of ≥100 mL / m 2 , or ≥110 mL / m 2 , or ≥120 mL / m 2 , or ≥130 mL / m 2 , or ≥135 mL / m 2 , or ≥140 mL / m 2 , or ≥145 mL / m 2 , or ≥150 mL / m 2 , or ≥155 mL / m 2 , or ≥160 mL / m 2 , or ≥165 mL / m 2 , or ≥170 mL / m 2 ; preferably ≥135mL / m 2 ; Alternatively, the heart failure patient has a baseline LVESVI of 100-350 mL / m 2 ; 110-350mL / m 2 120-350mL / m 2 ; 130-350mL / m 2 ; 135-350mL / m 2 ; preferably 135-350mL / m 2 .

22. The method according to any one of claims 18 to 21, wherein The heart failure patient is a chronic heart failure patient.

23. The method according to any one of claims 18 to 22, wherein The heart failure patients were classified as New York Heart Association (NYHA) II or III heart function classification.

24. The method according to any one of claims 18 to 23, wherein The NT-proBNP level in the plasma of the heart failure patient does not exceed 4000 pg / ml.

25. The method according to any one of claims 18 to 24, wherein Among the heart failure patients, the plasma NT-proBNP level of male patients does not exceed 1700 pg / ml; the plasma NT-proBNP level of female patients does not exceed 4000 pg / ml.

26. The method according to any one of claims 18 to 25, wherein Improving the cardiac function of patients with heart failure refers to improving LVESVI and / or LVEDVI.

27. The method according to any one of claims 18 to 26, wherein The heart failure patient's LVESVI decreased by equal to or greater than 10 mL / m after administration. 2 ; preferably equal to or greater than 20mL / m 2 .

28. The method according to any one of claims 18 to 27, wherein The heart failure patient's LVEDVI decreased by equal to or greater than 10 mL / m after administration. 2 ; preferably equal to or greater than 20mL / m 2 .

29. The method according to any one of claims 18 to 28, wherein The improving the cardiac function of a heart failure patient is to simultaneously improve the LVESVI and LVEDVI of a single heart failure patient.

30. The method of claim 29, wherein: The single heart failure patient simultaneously decreases LVESVI and LVEDVI by 20 or more or 25 mL / m after administration. 2 .

31. The use according to any one of claims 18 to 30, characterized in that The heart failure patient undergoes reverse ventricular remodeling.

32. The method according to any one of claims 18 to 31, wherein The neuregulins include neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).

33. The method according to any one of claims 18 to 31, wherein The neuregulin comprises neuregulin 1 (NRG-1) or an EGF-like region of NRG-1.

34. The method according to any one of claims 18 to 31, wherein The neuregulin is a protein with an amino acid sequence as shown in SEQ ID NO:

1.

35. The method according to any one of claims 18 to 34, wherein The method comprises administering a neuregulin to the patient via an induction course of therapy.

36. The method of claim 35, wherein: The lead-in dosing regimen comprises continuous administration of the pharmaceutical component for at least 3, 5, 7 or 10 days.

37. The method according to claim 35 or 36, wherein The method comprises administering maintenance therapy to the patient for at least 3, 6, or 12 months.

38. The method of claim 37, wherein: The maintenance course includes administering the drug every 3, 5, 7 or 10 days.

39. The method according to any one of claims 18 to 38, wherein The method further comprises the step of evaluating whether a patient in need of prevention, treatment, or delay of heart failure is suitable for treatment with neuregulin prior to administering the drug to the patient.

40. The method of claim 39, wherein The step of evaluating whether the patient is suitable for neuregulin therapy includes determining the NYHA cardiac function classification of the heart failure patient.

41. The method of claim 40, wherein: Patients with NYHA class II or NYHA class III heart function were evaluated as candidates for neuregulin therapy.

42. The method according to any one of claims 39 to 41, wherein The step of evaluating whether the patient is suitable for neuregulin therapy may further include measuring plasma NT-proBNP in the patient with heart failure.

43. The method of claim 42, wherein: The plasma NT-proBNP level does not exceed 4000 pg / ml.

44. The method according to claim 42 or 43, wherein The plasma NT-proBNP level of the male heart failure patient does not exceed 1700 pg / ml; the plasma NT-proBNP level of the female heart failure patient does not exceed 4000 pg / ml.

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