WO2024067817A1 - 神经调节蛋白及其应用 - Google Patents

神经调节蛋白及其应用 Download PDF

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WO2024067817A1
WO2024067817A1 PCT/CN2023/122655 CN2023122655W WO2024067817A1 WO 2024067817 A1 WO2024067817 A1 WO 2024067817A1 CN 2023122655 W CN2023122655 W CN 2023122655W WO 2024067817 A1 WO2024067817 A1 WO 2024067817A1
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heart failure
neuregulin
patient
patients
lvesvi
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PCT/CN2023/122655
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English (en)
French (fr)
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周明东
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上海泽生科技开发股份有限公司
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Publication of WO2024067817A1 publication Critical patent/WO2024067817A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • 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 human heart failure, and a method for using neuregulin to prevent, treat or delay human heart failure.
  • Heart failure is a syndrome of cardiac insufficiency caused by various heart diseases.
  • Current drugs for the treatment of HF mainly focus on angiotensin-converting enzyme (ACE) inhibitors, which are vasodilators that cause blood vessels to dilate, lower blood pressure, and reduce cardiac workload.
  • ACE angiotensin-converting enzyme
  • the percentage reduction in mortality after the use of ACE inhibitors is statistically significant, the actual mortality rate is only reduced by an average of 3%-4%, and there are some potential side effects.
  • Other options for preventing or treating HF also have corresponding limitations.
  • heart transplantation is obviously more expensive and invasive than drug treatment, and is further limited by the availability of donor hearts.
  • the use of mechanical devices, such as biventricular pacemakers is also invasive and relatively expensive. Therefore, due to the inadequacy of current treatments, people need new treatments.
  • NRG neuregulin
  • HRG glial growth factor
  • NDF neu differentiation factor
  • NRGs are involved in a range of biological responses: stimulating breast cancer cell differentiation and secretion of milk proteins; inducing neural crest cells to differentiate into Schwann cells; stimulating skeletal muscle cells to synthesize acetylcholine receptors; and promoting cardiomyocyte survival and DNA synthesis.
  • NRG1 plays an important role in the nervous system, heart and mammary gland, and there is evidence that NRG1 signaling plays a role in the development and function of several other organ systems and in the pathogenesis of human diseases, including schizophrenia and breast cancer.
  • NRG1 has many isoforms. Studies on mutant mice (knockout mice) have shown that different isoforms in the N-terminal region or epidermal growth factor (EGF)-like region have different functions in the body.
  • EGF epidermal growth factor
  • LVESVI left ventricular end-systolic volume index
  • the object of the present invention is to provide a method for improving cardiac function of patients with heart failure by using neuregulin, wherein the method uses a drug containing neuregulin in a special population suffering from chronic heart failure.
  • the present invention provides the use of neuregulin or its functional fragment, or nucleic acid encoding neuregulin or its functional fragment, or substance that increases the production and/or function of 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.
  • the present invention provides the 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.
  • the heart failure patient suffers from severe heart failure assessed by left ventricular function index.
  • the LVESVI value of the patient suffering from severe heart failure is at least 3 times the LVESVI value of a healthy individual.
  • the LVESVI value of the patient suffering from severe heart failure is at least 4 times the LVESVI value of a healthy individual.
  • the LVESVI value of the patient suffering from severe heart failure exceeds the LVESVI value of a healthy individual by 100 mL/m 2 .
  • the patient suffering from severe heart failure has a high LVESVI value of about the first 40% of all heart failure patients.
  • the patient suffering from severe heart failure has a LVESVI value 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 .
  • patients with severe heart failure have a LVESVI value greater than or equal to about 135 mL/m 2.
  • the patients with severe heart failure are people with severe ventricular remodeling.
  • the patients with severe heart failure are people with large hearts.
  • the present invention is used to prevent, treat or delay heart failure patients whose LVESVI 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.
  • heart failure patients have a LVESVI value of not less than about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165 or 170 mL/m 2 .
  • the heart failure patient is a patient with severe ventricular remodeling.
  • 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 ⁇ 135 mL/m 2 ;
  • the heart failure patient has a baseline LVESVI of 100-350 mL/m 2 ; 110-350 mL/m 2 ; 120-350 mL/m 2 ; 130-350 mL/m 2 ; 135-350 mL/m 2 ; preferably 135-350 mL/m 2 .
  • the heart failure patient is a chronic heart failure patient.
  • the heart failure patient has a New York Heart Association (NYHA) cardiac function classification of NYHA II or III, or the NT-proBNP level in plasma does not exceed 4000 pg/ml.
  • NYHA New York Heart Association
  • the NT-proBNP level in the plasma of male patients does not exceed 1700 pg/ml; and the NT-proBNP level in the plasma of female patients does not exceed 4000 pg/ml.
  • the improving cardiac function of patients with heart failure refers to improving LVESVI and/or LVEDVI.
  • the LVESVI of the heart failure patient decreases by 10 mL/m 2 or more; preferably by 20 mL/m 2 or more.
  • the LVEDVI of the heart failure patient decreases by 10 mL/m 2 or more; preferably by 20 mL/m 2 or more.
  • the improving cardiac function of a heart failure patient is to simultaneously improve LVESVI and LVEDVI of a single heart failure patient.
  • the single heart failure patient has both LVESVI and LVEDVI reduced by equal to or greater than 20 or 25 mL/m 2 .
  • the heart failure patient undergoes reverse ventricular remodeling.
  • the improvement in LVESVI and/or LVEDVI is achieved when neuregulin is administered for 10 days.
  • the neuregulin comprises neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).
  • the neuregulin comprises neuregulin 1 (NRG-1).
  • the neuregulin comprises an EGF-like region of neuregulin 1 (NRG-1).
  • the neuromodulatory protein is a protein whose amino acid sequence is shown in SEQ ID NO:1.
  • 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.
  • 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 patients in need.
  • the heart failure patient suffers from severe heart failure assessed by left ventricular function index.
  • the LVESVI value of the patient suffering from severe heart failure is at least 3 times the LVESVI value of a healthy individual.
  • the LVESVI value of the patient suffering from severe heart failure is at least 4 times the LVESVI value of a healthy individual.
  • the LVESVI value of the patient suffering from severe heart failure exceeds the LVESVI value of a healthy individual by 100 mL/m 2 .
  • the patient suffering from severe heart failure has a high LVESVI value in the top 40% of all heart failure patients.
  • the patient suffering from severe heart failure has a LVESVI value 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 of LVESVI value.
  • patients with severe heart failure have a LVESVI value greater than or equal to about 135 mL/m 2.
  • the patients with severe heart failure are people with severe ventricular remodeling.
  • the patients with severe heart failure are people with large hearts.
  • the present invention is used to prevent, treat, or delay cardiac arrest with a LVESVI greater than or equal to about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL/ m2 .
  • a heart failure patient has a LVESVI value of no less than about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mL/m 2 .
  • the heart failure patient is a patient with severe ventricular remodeling.
  • 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 ⁇ 135 mL/m 2 ;
  • the heart failure patient has a baseline LVESVI of 100-350 mL/m 2 ; 110-350 mL/m 2 ; 120-350 mL/m 2 ; 130-350 mL/m 2 ; 135-350 mL/m 2 ; preferably 135-350 mL/m 2 .
  • the heart failure patient is a chronic heart failure patient.
  • the heart failure patient has a New York Heart Association (NYHA) cardiac function classification of NYHA II or III, or the NT-proBNP level in plasma does not exceed 4000 pg/ml.
  • NYHA New York Heart Association
  • the NT-proBNP level in the plasma of male patients does not exceed 1700 pg/ml; and the NT-proBNP level in the plasma of female patients does not exceed 4000 pg/ml.
  • the improving cardiac function of patients with heart failure refers to improving LVESVI and/or LVEDVI.
  • the LVESVI of the heart failure patient decreases by 10 mL/m 2 or more; preferably by 20 mL/m 2 or more.
  • the LVEDVI of the heart failure patient decreases by 10 mL/m 2 or more; preferably by 30 mL/m 2 or more.
  • the improving cardiac function of a heart failure patient is to simultaneously improve LVESVI and LVEDVI of a single heart failure patient.
  • the single heart failure patient has both LVESVI and LVEDVI reduced by equal to or greater than 20 or 25 mL/m 2 .
  • said heart failure patient undergoes reverse heart failure remodeling.
  • the improvement in LVESVI and/or LVEDVI is achieved when neuregulin is administered for 10 days.
  • the method comprises administering neuregulin to the patient via an induction course of therapy.
  • the lead-in dosing regimen comprises continuous administration of the pharmaceutical composition for at least 3, 5, 7 or 10 days.
  • the method comprises administering a maintenance course of treatment to the patient for at least 3, 6 or 12 months.
  • the maintenance course comprises administering the drug every 3, 5, 7 or 10 days.
  • 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.
  • the step of assessing whether the patient is suitable for neuregulin therapy comprises evaluating the NYHA cardiac function rating of the heart failure patient.
  • patients with NYHA cardiac function class II or NYHA class III are suitable for Receive neuregulin therapy.
  • the step of assessing whether the patient is suitable for neuregulin therapy further comprises detecting plasma NT-proBNP in patients with heart failure.
  • the plasma NT-proBNP level does not exceed 4000 pg/ml.
  • 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.
  • the neuregulin comprises neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).
  • the neuregulin comprises neuregulin 1 (NRG-1).
  • the neuregulin comprises an EGF-like region of neuregulin 1 (NRG-1).
  • the neuromodulatory protein is a protein whose amino acid sequence is shown in SEQ ID NO:1.
  • the present invention provides a device for preventing, treating or delaying the onset of heart failure in patients, wherein the device is a device for improving LVESVI and/or LVEDVI in patients with heart failure, and the device comprises:
  • a treatment module which administers neuregulin treatment to patients who are suitable for neuregulin treatment based on whether the patient's NYHA cardiac function rating is NYHA class II or NYHA class III, or whether the patient's plasma NT-proBNP does not exceed 4000pg/ml, or whether the patient's LVESVI in the baseline period before administration is ⁇ 135mL/ m2 .
  • the device further comprises:
  • a detection module which performs NYHA cardiac function rating on the patient, or detects the plasma NT-proBNP level of the heart failure patient, or detects the baseline LVESVI value of the patient before drug administration;
  • An analysis and judgment module is used to analyze and judge 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 LVESVI in the baseline period before drug administration is ⁇ 135 mL/m 2 .
  • the neuromodulatory protein is a protein whose amino acid sequence is shown in SEQ ID NO:1.
  • the heart failure patients are those with severe ventricular remodeling.
  • the heart failure patient is a chronic heart failure patient.
  • the improving LVESVI and/or LVEDVI of a heart failure patient refers to reducing LVESVI and/or LVEDVI.
  • the LVESVI of the heart failure patient decreases by 10 mL/m 2 or more; preferably by 20 mL/m 2 or more.
  • the LVEDVI of the heart failure patient decreases by 10 mL/m 2 or more; preferably by 20 mL/m 2 or more.
  • the heart failure patient has a baseline LVESVI ⁇ 135 mL/m 2 before administration.
  • the heart failure patient is a heart failure patient with improved LVESVI and LVEDVI at the same time.
  • the LVESVI and LVEDVI of the heart failure patient are simultaneously reduced by equal to or greater than 20 or 25 mL/m 2 .
  • the heart failure patient undergoes reverse ventricular remodeling.
  • the improvement in LVESVI and/or LVEDVI is achieved when neuregulin is administered for 10 days.
  • the therapeutic module comprises a device for administering neuregulin to a patient via an infusion therapy procedure.
  • the therapeutic module comprises means for continuous administration of neuregulin for at least 3, 5, 7 or 10 days.
  • the treatment module includes means for maintaining the patient for a course of at least 3, 6 or 12 months.
  • the maintenance course comprises administering the drug every 3, 5, 7 or 10 days.
  • the neuregulin comprises neuregulin 1 (NRG-1), neuregulin 2 (NRG-2), neuregulin 3 (NRG-3), and neuregulin 4 (NRG-4).
  • the neuregulin comprises neuregulin 1 (NRG-1).
  • the neuregulin comprises an EGF-like region of neuregulin 1 (NRG-1).
  • the neuromodulatory protein is a protein whose amino acid sequence is shown in SEQ ID NO:1.
  • Figure 1 shows the proportion of patients with reduced and increased LVESVI at 30 days treated with Neulandin
  • Figure 2 shows the difference in LVESVI improvement compared with baseline between the neuregulin and placebo groups at 30 days;
  • Figure 3 shows the difference in LVESVI deterioration compared with baseline at day 30 between the neuregulin and placebo groups
  • Figure 4 shows the improvement of the cardiac function index LVESVI compared with the baseline at 30 days and 90 days;
  • FIG5 shows the difference in improvement in LVEDVI compared to baseline between the neuregulin and placebo groups at 30 days;
  • Figure 6 shows the difference between the neuregulin and placebo groups in the deterioration of LVEDVI compared to baseline at day 30;
  • FIG. 7 shows the results of significant improvements in both LVESVI and LVEDVI of individual subjects at 30 days.
  • FIG8 shows that neuregulin significantly improved LVESVI (LVESVI decreased by more than 13 mL/m 2) in the enriched subgroup population (baseline LVESVI ⁇ 135 mL/m 2 ) compared with the placebo group;
  • Figure 9 shows that Neuregulin significantly improved both LVESVI and LVEDVI in the enriched population (baseline LVESVI ⁇ 135 mL/m 2 ) (both indicators decreased by more than 20 mL/m 2 at the same time), which was significantly higher than that in the placebo group.
  • Figure 10 shows that the response rate of Neulandin for significantly improving both LVESVI and LVEDVI (both indicators decreased by more than 20 mL/m 2 at the same time) in the enriched population (baseline LVESVI ⁇ 135 mL/m 2 ) was higher than that in the whole population.
  • FIG11a shows that the mean improvement of LVESVI from baseline in the enriched population (baseline LVESVI ⁇ 135 mL/m 2 ) by neuregulin 30 days after administration was better than that in the whole population.
  • FIG11b shows that the mean improvement of LVEDVI from baseline in the enriched population (baseline LVESVI ⁇ 135 mL/m 2 ) by neuregulin 30 days after administration was better than that in the whole population.
  • 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.
  • NYHA New York Heart Association
  • the neuregulin of the present invention can improve the cardiac function of patients with heart failure or prevent and treat the deterioration of cardiac function, and the improvement of cardiac function includes a decrease in LVESVI and/or LVEDVI.
  • LVESVI and LVEDVI are greatly reduced at the same time in some individual subjects.
  • the higher the baseline level of LVESVI in the individual subject the greater the improvement in cardiac function.
  • the present invention is based on neuregulin 1 ⁇ (NRG1 ⁇ ).
  • Neuregulin 1 ⁇ is a transmembrane protein.
  • the extramembrane part is the N-terminus, including the immunoglobulin-like domain (Ig-like domain) and the EGF-like domain (EGF-like domain), and the intramembrane part is the C-terminus.
  • Ig-like domain immunoglobulin-like domain
  • EGF-like domain EGF-like domain
  • the intramembrane part is the C-terminus.
  • the extramembrane part of neuregulin can be enzymatically cleaved and is in a free state, which is conducive to binding to the ErbB receptors on the surface of surrounding cells and activating the corresponding cell signal transmission.
  • ErbB receptor family is also divided into four categories, ErbB1, ErbB2, ErbB3 and ErbB4, all of which are transmembrane proteins with a molecular weight of around 180-185KD. Except for ErbB2, they all contain ligand binding regions at the N-terminal outside the membrane; except for ErbB3, they all contain protein tyrosine kinase activity at the C-terminal inside the membrane. Among them, ErbB1 is a receptor for epidermal growth factor, and ErbB3 and ErbB4 are both receptors for neuregulin. Among the receptors for neuregulin, only ErbB2 and ErbB4 are highly expressed in the heart.
  • neuregulin When neuregulin binds to the extracellular part of ErbB3 or ErbB4, it causes ErbB3, ErbB4 to form heterodimers with other ErbB receptors (often including ErbB2), or ErbB4 to form homodimers with itself, which then leads to receptor activation.
  • the intramembrane part of the protein is phosphorylated.
  • the phosphorylated intramembrane part can further bind to a variety of signal transduction proteins in the cell, thereby activating the downstream ERK or AKT signaling pathway, causing a series of cellular responses: including stimulation or inhibition of cell proliferation, cell apoptosis, cell migration, cell differentiation or cell adhesion.
  • NRG-1 ⁇ neuregulin-1 ⁇
  • ErbB2 can form heterodimers with ErbB3 or ErbB4 and its affinity is higher than that of ErbB3 or ErbB4 homodimers.
  • NRG-1 ⁇ neuregulin-1 ⁇
  • ErbB2 can form heterodimers with ErbB3 or ErbB4 and its affinity is higher than that of ErbB3 or ErbB4 homodimers.
  • Results of neurodevelopmental studies suggest that the formation of the sympathetic nervous system requires an intact NRG-1 ⁇ , ErbB2, and ErbB3 signaling system.
  • Targeted disruption of NRG-1 ⁇ , or ErbB2 or ErbB4 results in embryonic lethality due to defects in cardiac development.
  • Recent studies have also highlighted the important roles of NRG-1 ⁇ , ErbB2, and ErbB4 in cardiovascular development and in maintaining normal adult cardiac function. Studies have shown that NRG-1 ⁇ can enhance the organization of the sarcomere in adult cardiomyocytes.
  • Neuregulin or “neuregulin” or “NRG” refers to a protein or polypeptide that can bind to and activate ErbB2, ErbB3, ErbB4 or their heterodimers or homodimers, including isoforms of neuregulin, EGF-like functional domains in neuregulin, polypeptides containing 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.
  • neuregulin is a protein or polypeptide that can bind to and activate ErbB2/ErbB4 or ErbB2/ErbB3 heterodimers.
  • the neuregulin of the present invention is a fragment of the NRG-1 ⁇ 2 isomer, i.e., a fragment of amino acids 177-237, which contains an EGF-like functional domain.
  • the amino acid sequence of the 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.
  • the "epidermal growth factor-like domain” or “EGF-like region” or “EGF-like domain” used herein 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.
  • the EGF-like domain binds to and activates ErbB2/ErbB4 or ErbB2/ErbB3 heterodimers.
  • the EGF-like domain comprises amino acids from the receptor binding region of NRG-1.
  • the EGF-like domain refers to amino acids 177-226, 177-237, or 177-240 of NRG-1.
  • the EGF-like domain comprises amino acids of the receptor binding region of NRG-2. In certain embodiments, the EGF-like domain comprises The amino acids of the receptor binding region of NRG-3. In certain embodiments, the EGF-like domain comprises the amino acids of 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).
  • treatment refers to any means by which the symptoms of discomfort, disorder or disease can be improved or altered for the better.
  • the effect can be preventive, which completely or partially prevents a disease or its symptoms from occurring, or therapeutic, which partially or completely cures a disease and/or the adverse effects caused by the disease.
  • Treatment also includes any pharmaceutical use of the compositions described herein.
  • heart failure refers to an abnormality in cardiac function in which the heart is unable to supply blood to meet the metabolic needs of the tissues.
  • 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, etc.
  • 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 cause cardiac arrest.
  • LVESVI refers to Left Ventricular End-Systolic Volume Index.
  • LVEDVI refers to Left Ventricular End-Diastolic Volume Index.
  • the left ventricular end-systolic volume index is the volume of the left ventricle at its smallest contraction/body surface area, making the evaluation of the left ventricular end-systolic volume unaffected by differences in 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, LVESVI is usually in the range of 8 to 27 mL/m 2 for women and 9 to 31 mL/m 2 for men.
  • LVEDVI Left ventricular end-diastolic volume index
  • 2D ECHO two-dimensional ECHO
  • 3D ECHO three-dimensional ECHO
  • CMR cardiac magnetic resonance imaging
  • LVEDVI is usually in the range of 29 to 70 mL/m 2 for women and 30 to 79 mL/m 2 for men.
  • Cardiac systolic function is related to factors such as preload, afterload, contractility and myocardial weight.
  • LVESVI is an indicator for judging systolic function and prognosis.
  • the simultaneous decrease of LVEDVI and LVESVI to a certain extent in the same individual is clear and definite evidence, indicating that the patient's myocardial contractility is enhanced, cardiac function is improved, and ventricular remodeling is reversed, which can effectively reduce the mortality of patients with heart failure.
  • N-terminal pro-brain natriuretic peptide or “NT-proBNP” refers to the inactive pro-fragment of N-terminal pro-brain natriuretic peptide (BNP).
  • Pro-BNP is the precursor of BNP, which is a hormone-related active natriuretic peptide that is mainly released by myocardial cells in the left ventricular wall. Under the expansion and contraction of the myocardial wall, the pro-hormone proBNP is cleaved by proteases and split into BNP and inactive pro-BNP.
  • NT-proBNP is the precursor of BNP, which is a hormone-related active natriuretic peptide that is mainly released by myocardial cells in the left ventricular wall. Under the expansion and contraction of the myocardial wall, the pro-hormone proBNP is cleaved by proteases and split into BNP and inactive pro-BNP.
  • the levels of BNP and NT-proBNP in plasma can be used to screen for, diagnose, and establish a prognosis for heart failure, as both markers are typically elevated in patients whose condition worsens.
  • the methods of the present invention include using BNP or NT-proBNP levels to indicate a patient who is suitable for treatment of heart failure with neuregulin.
  • the "New York Heart Association” or “NYHA” cardiac function classification used in this article is a method for classifying the degree of heart failure. It divides patients into 4 categories according to the degree of limitation of their physical activity ability. Limitation or symptoms refers to normal breathing and varying degrees of dyspnea and/or angina: I, asymptomatic and ordinary activity is not limited, such as dyspnea when walking, climbing stairs, etc.; II, mild symptoms (mild dyspnea and/or angina) and ordinary activities are slightly limited; III, physical activity is significantly limited, even in the case of less than normal activity, for example, short-distance walking (20-100m), resting fashion feels comfortable; IV, severely limited activity, even at rest there are symptoms, most patients are bedridden.
  • I asymptomatic and ordinary activity is not limited, such as dyspnea when walking, climbing stairs, etc.
  • II mild symptoms (mild dyspnea and/or angina) and ordinary activities are slightly limited
  • III physical activity is significantly limited, even in
  • the neuregulin of the present invention can improve the cardiac function of patients with heart failure, especially simultaneously improve the LVESVI and LVEDVI of a single heart failure patient; at the same time, the present invention surprisingly found that the neuregulin can unexpectedly improve the cardiac function of heart failure patients with high baseline LVESVI values, especially heart failure patients with LVESVI ⁇ 135mL/ m2 , and its effect is better than the improvement of the cardiac function of all heart failure patients.
  • the effect of the neuregulin of the present invention on improving the cardiac function of patients with heart failure can be maintained for a long time, for example, up to 90 days after administration;
  • the neuregulin of the present invention directly acts on myocardial cells, repairs the damaged structure and function thereof, enhances myocardial contractility, and reverses ventricular remodeling.
  • 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.
  • the experiment in this example adopts a multicenter, randomized, double-blind, placebo-controlled parallel study based on standard treatment to evaluate the effect of recombinant human neuregulin for injection on the cardiac function of chronic systolic heart failure patients with male NT-proBNP ⁇ 1700pg/ml and female NTproBNP ⁇ 4000pg/ml, New York Heart Association grade II-III, and confirm its efficacy and safety.
  • Experimental group recombinant human neuregulin for injection + standard basic treatment drugs ( ⁇ -blockers, ACEI/ARB/ARNI, aldosterone receptor antagonists, etc.).
  • Placebo group placebo + standard basic treatment drugs ( ⁇ -blockers, ACEI/ARB/ARNI, aldosterone receptor antagonists, etc.).
  • the improvement values of LVESVI compared with the baseline at 30 days after administration were stratified (greater than or equal to 5, 10, 15, 20, 25, 30, 35, 40 ml/m 2 ), and the improvement rates of the neuregulin group and the placebo group at each level were calculated.
  • the LVESVI decreased by 5, 10, 15, 20, 25, 30, 35, 40 ml/m 2 compared with the baseline, the corresponding improvement rates of the neuregulin group were 45.2%, 34.2%, 23.3%, 17.8%, 15.1%, 8.2%, 5.5%, 2.7%, respectively; the corresponding improvement rates of the placebo group were: 52.7%, 31.1%, 16.2%, 5.4%, 2.7%, 2.7%, 2.7%, 2.7%, 2.7%, respectively.
  • the proportion of improved patients in the neuregulin group showed a significant difference from that in the placebo group, indicating that neuregulin was superior to placebo in improving LVESVI.
  • the LVESVI improvement was greater than or equal to 20 and 25 ml/ m2 , the difference in improvement rate between the two groups was statistically significant (P ⁇ 0.05, see Figure 2).
  • the natural occurrence rate of patients with LVESVI reduction of more than 25ml/ m2 within 1 month was 2.58%, which was close to the proportion of patients with improvement of more than 25ml/ m2 in the placebo group within 1 month after medication (2.7%), indicating that the improvement rate of LVESVI improvement of more than 25ml/ m2 within one month was stable, and the improvement rate of the Neuland Green group to achieve this improvement within one month was 15.1%, which was significantly higher than the natural level.
  • the medication can significantly improve the rate of substantial improvement in the subjects' cardiac function.
  • N number of subjects in the group who obtained LVESVI indicators
  • n number of specific categories
  • the proportion of people with LVEDVI reduction from baseline in 30 days was higher than that in the placebo group.
  • LVEDVI decreased by 5, 10, 15, 20, 25, 30, 35, and 40 ml/m2 compared with baseline 30 days after administration.
  • the corresponding improvement rates in the Neuregrin group were 43.8%, 30.1%, 21.9%, 17.8%, 16.4%, 13.7%, 6.8%, and 5.5%, respectively;
  • the corresponding improvement rates in the placebo group were: 44.6%, 29.7%, 14.9%, 12.2%, 6.8%, 4.1%, 4.1%, and 2.7%, respectively.
  • N number of subjects in the group who obtained LVESVI indicators
  • n number of specific categories
  • N number of subjects in the group who obtained LVESVI indicators
  • n number of specific categories
  • the LVESVI and LVEDVI of a single individual decreased by greater than or equal to 5, 10, 15, 20, 25, 30, 35, and 40 ml/ m2 compared with the baseline.
  • 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; the corresponding improvement rates in the placebo group were 39.2%, 20.3%, 12.2%, 2.7%, 2.7%, 2.7%, 2.7%, and 1.4%, respectively.
  • the subjects' individual LVESV and LVEDV were improved simultaneously, especially when LVESVI and LVEDV were reduced by 20 ml/ m2 at the same time, there were 12 subjects in the neuregulin group with an improvement rate of 16.4%, and there were 2 subjects in the placebo group with an improvement rate of 2.7%, with a p value of 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.
  • LVESVI and LVEDVI decreased by 5, 10, 15, 20, 25, 30, 35, 40 ml/m 2 (FAS) in a single individual at 30 days compared with baseline
  • N number of subjects in the group who obtained LVESVI indicators
  • n number of specific categories
  • LVESVI and LVEDVI increased by 5, 10, 15, 20, 25, 30 ml/m 2 (FAS) at 30 days compared with baseline
  • N number of subjects in the group who obtained LVESVI indicators
  • n number of specific categories
  • the enriched population here refers to patients with baseline LVESVI ⁇ 135 mL/m 2 , which accounts for about 41% of all the subjects. These patients generally suffer from severe heart failure and severe ventricular remodeling.
  • the response rate of the Neuregrin group for significant improvement in LVESVI in the enriched subgroup population reached 50%, which was significantly higher than that in the placebo group.
  • Example 1 By statistically analyzing the test results of Example 1, the present inventors studied the response rate of neuregulin in enriched patient populations with simultaneous improvement in LVESVI and LVEDVI (both exceeding 20 mL/m 2 ).
  • the present invention surprisingly found that although the number of patients in the Newcadin-treated group who simultaneously experienced substantial improvements in LVESVI and LVEDVI was significantly higher than that in the placebo group in both the whole population and the enriched population, the Newcadin-treated group in the enriched population had a better response rate in terms of substantial improvements in LVESVI and LVEDVI (both indicators were reduced by more than 20mL/ m2 at the same time) than the Newcadin-treated group in the whole population. As shown in Figure 10.
  • the present invention further counted the mean improvement of LVESVI or LVEDVI relative to baseline 30 days after administration of Newcadin or placebo in the whole population and the enriched population. It was also surprisingly found that although the mean improvement of LVESVI or LVEDVI relative to baseline in the Newcadin-treated group of patients in the whole population and the enriched population was better than that in the placebo group, the Newcadin-treated group in the enriched population had a better mean improvement of LVESVI or LVEDVI relative to baseline than the Newcadin-treated group in the whole population. As shown in Figures 11a and 11b. These results all suggest that Newcadin has a better effect on improving the cardiac function of this part of the enriched population, and is more effective in preventing, treating heart failure or delaying the onset of heart failure for this part of the enriched population.
  • Neuregulin has better efficacy in the enriched population (baseline LVESVI ⁇ 135 mL/m 2 ): the response rate of the drug-treated group with LVESVI improvement greater than 13 mL/m 2 reached 50%, which was statistically significant; the response rate of individual subjects with simultaneous improvement of LVESVI and LVEDVI greater than 20 mL/m 2 reached 26.5% (placebo was 0%, which was statistically significant).

Abstract

利用神经调节蛋白或其功能片段，或编码神经调节蛋白或其功能片段的核酸，或提高神经调节蛋白在人体内的产量和/或功能的物质来预防、治疗或延迟心衰患者发病的药物中的用途，所述药物能改善心衰患者的心功能，逆转心室重构。还提供了预防、治疗心衰患者或延迟心衰患者发病的方法和设备。

Description

神经调节蛋白及其应用 技术领域
本发明涉及医学领域。具体地说，本发明涉及神经调节蛋白在制备用于预防、治疗或延缓人类心力衰竭的药物中的应用，以及利用神经调节蛋白预防、治疗或延缓人类心力衰竭的药物的方法。
背景技术
心力衰竭(heart failure，HF)是各种心脏疾病导致心功能不全的一种综合征。目前治疗心衰的药物主要集中于血管紧张素转化酶(ACE)抑制剂，这些血管舒张剂引起血管扩张、降低血压并减少心脏负荷。虽然使用ACE抑制剂后死亡率的百分数下降是具有统计学差异的，但实际的死亡率仅平均下降3％-4％，并且还有一些潜在的副作用。其他预防或治疗心衰的选择亦有相应的局限。比如，心脏移植显然比药物治疗更昂贵且更具侵入性，并且还进一步受有无供体心脏的限制。使用机械装置，比如双心室心脏起搏器，同样具有侵入性并且比较昂贵。因此，由于当前治疗手段的不足，人们需要有新的治疗方法。
一种很有前途的新的治疗手段涉及给心衰患者或有心衰风险的患者施用神经调节蛋白(neuregulin，NRG，纽兰格林；heregulin，HRG)，又称为神经胶质生长因子(glial growth factor，GGF)，neu分化因子(new differentiation factor，NDF)。这是分子量在44KD左右的糖蛋白，它们在细胞间传递信号，是酪氨酸激酶受体ErbB家族的配体。神经调节蛋白家族含4个成员：NRG1、NRG2、NRG3、NRG4。NRGs涉及一系列生物学反应：刺激乳腺癌细胞分化和分泌乳汁蛋白；诱导神经嵴细胞分化成Schwann细胞；刺激骨骼肌细胞合成乙酰胆碱受体；并且促进心肌细胞成活和DNA合成。用纽兰格林基因严重缺陷的纯合子小鼠胚胎做活体研究证明纽兰格林对于心脏和神经发育是必须的。NRG1在神经系统、心脏和乳腺中起着重要作用，还有证据显示NRG1信号传递在其他一些器官系统的发育、功能以及人类疾病(包括精神分裂症和乳腺癌)的发病机理中起作用。NRG1有很多异构体。对基因突变小鼠(基因敲除小鼠)的研究说明在N末端区或表皮生长因子(EGF)类似区不同的异构体，其在体功能也不一样。
虽然目前对神经调节蛋白的功能已有各种研究，但是如何使用神经调节蛋白，以及如何在一些亚人群上取得更好的治疗效果，还需要更多的研究。
另外，左心室(LV)功能评估是心脏病患者临床决策的重要组成部分。特别是，左心室收缩末期容积指数(LVESVI)是衡量心脏左室功能的指标，LVESVI增加与死亡或住院等不良事件发生率增加相关。目前，LVESVI值特别高(如超过135mL/m2)的心力衰竭患者预后较差，文献中尚无此类患者治疗的具体报道。LVESVI值特别高的心力衰竭患者的治疗仍然是一个未被满足的需求和重大的医学挑战。
发明内容
本发明的目的是提供利用神经调节蛋白改善心力衰竭患者心功能的方法，该方法在患有慢性心力衰竭的特殊人群中使用包含纽兰格林蛋白的药物。
在第一方面，本发明提供神经调节蛋白或其功能片段，或编码神经调节蛋白或其功能片段的核酸，或提高神经调节蛋白在人体内的产量和/或功能的物质在制备预防、治疗心衰患者或延迟心衰患者发病的药物中的用途，所述药物能改善心衰患者的心功能。
本发明提供神经调节蛋白在制备预防、治疗心衰患者，延迟心衰患者发病，或者改善心衰患者的心功能的药物中的用途。
在一些实施方式中，心衰患者患有通过左心室功能指标评估的严重心力衰竭。在一些实施方式中，例如，患有严重心力衰竭的患者的LVESVI值是健康个体的LVESVI值的至少3倍。在一些实施方式中，例如，患有严重心力衰竭的患者的LVESVI值是健康个体的LVESVI值的至少4倍。在一些实施例中，例如，患有严重心力衰竭的患者的LVESVI值超过健康个体的LVESVI值100mL/m2。在一些实施方式中，例如，患有严重心力衰竭的患者具有处于所有心力衰竭患者的约前40％高的LVESVI值。在一些实施方式中，例如，患有严重心力衰竭的患者具有大于或等于约100、105、110、115、120、125、130、135、140、145、150、155、160、165或170mL/m2的LVESVI值。在一些实施方式中，例如，患有严重心力衰竭的患者具有大于或等于约135mL/m2的LVESVI值。在一些实施方式中，上述这些患有严重心力衰竭的患者是心室重构严重的人群。在一些实施方式中，上述这些患有严重心力衰竭的患者是具有大心脏的人群。
在一些实施方式中，例如，本发明用于预防、治疗或延迟LVESVI大于或等于约100、105、110、115、120、125、130、135、140、145、150、155、160、165或170mL/m2的心衰患者。在一些实施方式中，例如，心力衰竭患者具有不小于约100、105、110、115、120、125、130、135、140、145、150、155、160、165或170mL/m2的LVESVI值。
在一些实施方式中，所述心衰患者是心室重构严重人群。
在一些实施方式中，所述心衰患者在给药前的基线期LVESVI≥100mL/m2，或≥110mL/m2，或≥120mL/m2，或≥130mL/m2，或≥135mL/m2，或≥140mL/m2，或≥145mL/m2，或≥150mL/m2，或≥155mL/m2，或≥160mL/m2，或≥165mL/m2，或≥170mL/m2；优选≥135mL/m2；
或者，所述心衰患者在给药前的基线期LVESVI在100-350mL/m2；110-350mL/m2；120-350mL/m2；130-350mL/m2；135-350mL/m2；优选135-350mL/m2。
在优选的实施方式中，所述心衰患者是慢性心衰患者。
在优选的实施方式中，所述心衰患者通过纽约心脏协会(NYHA)心功能分级为NYHA II或III，或者血浆中NT-proBNP水平不超过4000pg/ml。
在优选的实施方式中，所述心衰患者中，男性患者的血浆中NT-proBNP水平不超过1700pg/ml；女性患者的血浆中NT-proBNP水平不超过4000pg/ml。
在优选的实施方式中，所述改善心衰患者的心功能是指改善LVESVI和/或LVEDVI。
在具体的实施方式中，所述心衰患者LVESVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
在具体的实施方式中，所述心衰患者LVEDVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
在具体的实施方式中，所述改善心衰患者的心功能是同时改善单个心衰患者的LVESVI和LVEDVI。
在具体的实施方式中，所述单个心衰患者LVESVI和LVEDVI同时降低等于或大于20或25mL/m2。
在具体实施方式中，所述心衰患者发生逆转心室重构。
在优选的实施方式中，所述LVESVI和/或LVEDVI的改善是在神经调节蛋白给药10天的情况下取得的。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)，神经调节蛋白2(NRG-2)，神经调节蛋白3(NRG-3)，和神经调节蛋白4(NRG-4)。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)的EGF样类似区。
在一些实施方式中，所述神经调节蛋白是氨基酸序列如SEQ ID NO:1所示的蛋白。
在第二方面，本发明提供一种预防、治疗心衰患者或延迟心衰患者发病的方法，包括对需要的患者施用有效量的神经调节蛋白或其功能片段，或编码神经调节蛋白或其功能片段的核酸，或提高神经调节蛋白产量和/或功能的物质，所述方法能改善心衰患者的心功能。
本发明提供一种预防、治疗心衰患者，延迟心衰患者发病或者改善心衰患者的心功能的方法，包括对需要的患者施用有效量的神经调节蛋白。
在一些实施方式中，心衰患者患有通过左心室功能指标评估的严重心力衰竭。在一些实施方式中，例如，患有严重心力衰竭的患者的LVESVI值是健康个体的LVESVI值的至少3倍。在一些实施方式中，例如，患有严重心力衰竭的患者的LVESVI值是健康个体的LVESVI值的至少4倍。在一些实施例中，例如，患有严重心力衰竭的患者的LVESVI值超过健康个体的LVESVI值100mL/m2。在一些实施方式中，例如，患有严重心力衰竭的患者具有处于所有心力衰竭患者的前40％高的LVESVI值。在一些实施方式中，例如，患有严重心力衰竭的患者具有大于或等于约100、105、110、115、120、125、130、135、140、145、150、155、160、165或170mL/m2的LVESVI值。在一些实施方式中，例如，患有严重心力衰竭的患者具有大于或等于约135mL/m2的LVESVI值。在一些实施方式中，上述这些患有严重心力衰竭的患者是心室重构严重的人群。在一些实施方式中，上述这些患有严重心力衰竭的患者是具有大心脏的人群。
在一些实施方式中，例如，本发明用于预防、治疗或延迟LVESVI大于或等于约100、105、110、115、120、125、130、135、140、145、150、155、160、165或170mL/m2的心 衰患者。在一些实施方式中，例如，心力衰竭患者具有不小于约100、105、110、115、120、125、130、135、140、145、150、155、160、165或170mL/m2的LVESVI值。
在一些实施方式中，所述心衰患者是心室重构严重人群。
在一些实施方式中，所述心衰患者在给药前的基线期LVESVI≥100mL/m2，或≥110mL/m2，或≥120mL/m2，或≥130mL/m2，或≥135mL/m2，或≥140mL/m2，或≥145mL/m2，或≥150mL/m2，或≥155mL/m2，或≥160mL/m2，或≥165mL/m2，或≥170mL/m2；优选≥135mL/m2；
或者，所述心衰患者在给药前的基线期LVESVI在100-350mL/m2；110-350mL/m2；120-350mL/m2；130-350mL/m2；135-350mL/m2；优选135-350mL/m2。
在优选的实施方式中，所述心衰患者是慢性心衰患者。
在优选的实施方式中，所述心衰患者通过纽约心脏协会(NYHA)心功能分级为NYHA II或III，或者血浆中NT-proBNP水平不超过4000pg/ml。
在优选的实施方式中，所述心衰患者中，男性患者的血浆中NT-proBNP水平不超过1700pg/ml；女性患者的血浆中NT-proBNP水平不超过4000pg/ml。
在优选的实施方式中，所述改善心衰患者的心功能是指改善LVESVI和/或LVEDVI。
在具体的实施方式中，所述心衰患者LVESVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
在具体的实施方式中，所述心衰患者LVEDVI降低等于或大于10mL/m2；优选等于或大于30mL/m2。
在具体的实施方式中，所述改善心衰患者的心功能是同时改善单个心衰患者的LVESVI和LVEDVI。
在具体的实施方式中，所述单个心衰患者LVESVI和LVEDVI同时降低等于或大于20或25mL/m2。
在具体的实施方式中，所述心衰患者发生逆转心衰重构。
在优选的实施方式中，所述LVESVI和/或LVEDVI的改善是在神经调节蛋白给药10天的情况下取得的。
在优选的实施方式中，所述方法包括将神经调节蛋白通过导入疗程施用于患者。
在优选的实施方式中，所述导入疗程给药方案包括连续施用该药物组分至少3、5、7或10天。
在优选的实施方式中，所述方法包括对病人进行至少3、6或12个月的维持疗程。
在优选的实施方式中，所述维持疗程包括每3、5、7或10天施用该药物。
在优选的实施方式中，所述方法还包括在对需要预防、治疗或延迟心力衰竭的患者给药前评估所述患者是否适合接受神经调节蛋白治疗的步骤。
在优选的实施方式中，评估所述患者是否适合接受神经调节蛋白治疗的步骤包括对心衰患者作NYHA心脏功能评级。
在优选的实施方式中，NYHA心脏功能评级为NYHA II级或NYHA III级的患者适合 接受神经调节蛋白治疗。
在优选的实施方式中，评估所述患者是否适合接受神经调节蛋白治疗的步骤还包括检测心衰患者的血浆NT-proBNP。
在优选的实施方式中，所述血浆NT-proBNP水平不超过4000pg/ml。
在优选的实施方式中，所述男性心衰患者的血浆NT-proBNP水平不超过1700pg/ml；所述女性心衰患者的血浆NT-proBNP水平不超过4000pg/ml。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)，神经调节蛋白2(NRG-2)，神经调节蛋白3(NRG-3)，和神经调节蛋白4(NRG-4)。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)的EGF样类似区。
在一些实施方式中，所述神经调节蛋白是氨基酸序列如SEQ ID NO:1所示的蛋白。
在第三方面，本发明提供一种用于预防、治疗心衰患者或延迟心衰患者发病的设备，所述设备是改善心衰患者的LVESVI和/或LVEDVI的设备，所述设备包括：
治疗模块，所述模块根据所述患者的NYHA心脏功能评级是否为NYHA II级或NYHA III级，或者所述患者的血浆NT-proBNP是否不超过4000pg/ml，或者所述患者在给药前的基线期LVESVI是否≥135mL/m2对适合接受神经调节蛋白治疗的患者施以神经调节蛋白治疗。
在优选的实施方式中，所述设备还包括：
检测模块，所述模块对患者作NYHA心脏功能评级，或者检测心衰患者的血浆NT-proBNP水平，或者检测所述患者在给药前的基线期LVESVI数值；和
分析判断模块，所述模块分析和判断所述患者的NYHA心脏功能评级是否为NYHA II级或NYHA III级，或者所述患者的血浆NT-proBNP是否不超过4000pg/ml，或者所述患者在给药前的基线期LVESVI是否≥135mL/m2。
在优选的实施方式中，所述男性心衰患者的血浆NT-proBNP水平不超过1700pg/ml；所述女性心衰患者的血浆NT-proBNP水平不超过4000pg/ml。
在优选的实施方式中，所述神经调节蛋白是氨基酸序列如SEQ ID NO:1所示的蛋白。
在优选的实施方式中，所述心衰患者是心室重构严重人群。
在优选的实施方式中，所述心衰患者是慢性心衰患者。
在优选的实施方式中，所述改善心衰患者的LVESVI和/或LVEDVI是指降低LVESVI和/或LVEDVI。
在优选的实施方式中，所述心衰患者LVESVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
在优选的实施方式中，所述心衰患者LVEDVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
在优选的实施方式中，所述心衰患者在给药前的基线期LVESVI≥135mL/m2。
在优选的实施方式中，所述心衰患者是同时改善LVESVI和LVEDVI的心衰患者。
在优选的实施方式中，所述心衰患者LVESVI和LVEDVI同时降低等于或大于20或25mL/m2。
在优选的实施方式中，所述心衰患者发生逆转心室重构。
在优选的实施方式中，所述LVESVI和/或LVEDVI的改善是在神经调节蛋白给药10天的情况下取得的。
在优选的实施方式中，所述治疗模块包括将神经调节蛋白通过导入疗程施用于患者的器件。
在优选的实施方式中，所述治疗模块包括连续施用神经调节蛋白至少3、5、7或10天的器件。
在优选的实施方式中，所述治疗模块包括对病人进行至少3、6或12个月的维持疗程的器件。
在优选的实施方式中，所述维持疗程包括每3、5、7或10天施用该药物。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)，神经调节蛋白2(NRG-2)，神经调节蛋白3(NRG-3)，和神经调节蛋白4(NRG-4)。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)。
在一些实施方式中，所述神经调节蛋白包含神经调节蛋白1(NRG-1)的EGF样类似区。
在一些实施方式中，所述神经调节蛋白是氨基酸序列如SEQ ID NO:1所示的蛋白。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了30天时LVESVI缩小及增大的患者在纽兰格林中占比；
图2显示了30天时，相比于基线的LVESVI改善效果在纽兰格林和安慰剂组间的差异；
图3显示了30天时，相比于基线的LVESVI恶化情况在纽兰格林和安慰剂组间的差异；
图4显示了30天、90天时，心功能指标LVESVI相比于基线的改善效果；
图5显示了30天时，相比于基线的LVEDVI的改善效果在纽兰格林和安慰剂组间的差异；
图6显示了30天时，相比于基线LVEDVI的恶化情况在纽兰格林和安慰剂组间的差异；
图7显示了30天时，受试者个体的LVESVI与LVEDVI同时大幅改善的结果。
图8显示纽兰格林对富集亚组人群(基线期LVESVI≥135mL/m2)的LVESVI大幅改善(LVESVI降低13mL/m2以上)显著高于安慰剂组；
图9显示纽兰格林对富集人群(基线期LVESVI≥135mL/m2)的LVESVI及LVEDVI同时大幅改善(两项指标同时降低20mL/m2以上)显著高于安慰剂组。
图10显示纽兰格林对富集人群(基线期LVESVI≥135mL/m2)的LVESVI及LVEDVI同时大幅改善(两项指标同时降低20mL/m2以上)的应答率高于全人群。
图11a显示用药后30日纽兰格林对富集人群(基线期LVESVI≥135mL/m2)的LVESVI相对基线的改善均值好于全人群。
图11b显示用药后30日纽兰格林对富集人群(基线期LVESVI≥135mL/m2)的LVEDVI相对基线的改善均值好于全人群。
具体实施方式
本发明包括，通过纽约心脏协会(NYHA)心功能分级和/或检测患者血浆中NT-proBNP水平筛选出来的心衰病人经神经调节蛋白治疗后能够取得显著的疗效。
本发明所述神经调节蛋白能改善心力衰竭患者心脏功能或防治心功能恶化，所述心功能改善包括LVESVI和/或LVEDVI降低。在具体的实施方式中，部分受试者个体中LVESVI和LVEDVI同时大幅降低。在其它实施方式中，受试者个体LVESVI基线期水平越高，心功能改善越大。
除非特别说明，本发明中使用的所有技术术语和科学术语都为本发明所属技术领域的普通技术人员通常所理解的。所有专利文献、专利申请文献、公开的专利文献和其它出版物均作为参考。如本节阐述的定义与上述参考文献所述的定义不一致或相反时，以本节阐述的定义为准。
除非在上下文中明确表明，否则本说明书及其所附权利要求书中，所用的单数形式“一个”、“一种”和“该”包括相应的复数参考，并与“至少一个”或“一个或多余一个”可互换使用。
本发明以神经调节蛋白1β(NRG1β)为基础。神经调节蛋白1β为一跨膜蛋白-。膜外部分是N末端，包括免疫球蛋白类似区(Ig-like domain)和EGF类似区(EGF-like domain)，膜内部分是C末端。在细胞外基质的金属蛋白酶作用下，神经调节蛋白的膜外部分可被酶切下来而呈游离状态，从而有利于和周围细胞表面的ErbB受体结合，激活相应的细胞信号传递。
ErbB受体家族也分为四类，ErbB1、ErbB2、ErbB3和ErbB4，它们都是跨膜蛋白，分子量在180-185KD附近。除ErbB2外，它们在膜外的N末端都含配体结合区；除ErbB3外，它们在膜内的C末端都含蛋白酪氨酸激酶活性。其中ErbB1是表皮生长因子的受体，ErbB3和ErbB4都是神经调节蛋白的受体。在神经调节蛋白的受体中，只有ErbB2和ErbB4在心脏表达量较高。
当神经调节蛋白与ErbB3或ErbB4的膜外部分结合时，将引起ErbB3、ErbB4与其他ErbB受体(常常包括ErbB2)形成异源二聚体，或ErbB4自身形成同源二聚体，然后导致受体 的膜内部分被磷酸化。磷酸化的膜内部分可进一步与细胞内的多种信号传递蛋白结合，从而激活下游ERK或AKT信号通路，引起一系列细胞反应：包括刺激或抑制细胞增殖、细胞凋亡、细胞迁移、细胞分化或细胞粘连。
已有研究表明NRG-1的EGF样类似区，约50至64个氨基酸，足以结合并活化这些受体。以前的研究表明纽兰格林-1β(NRG-1β)能以高亲和力直接结合ErbB3和ErbB4。孤儿受体ErbB2能与ErbB3或ErbB4形成异源二聚体并且其亲和力比ErbB3或ErbB4同源二聚体要高。神经发育的研究结果提示交感神经系统的形成需要完整的NRG-1β、ErbB2和ErbB3信号传导系统。靶向破坏NRG-1β、或ErbB2或ErbB4后由于心脏发育缺陷而导致胚胎致死。最近的研究也突显了NRG-1β、ErbB2和ErbB4在心血管发育以及维持成年正常心脏功能方面具有重要作用。研究表明NRG-1β能增强成年心肌细胞的肌小节的组织结构。
本文所用的“神经调节蛋白”或“neuregulin”或“NRG”是指能够结合并激活ErbB2、ErbB3、ErbB4或其异源或同源二聚体的蛋白或多肽，包括神经调节蛋白的异构体、神经调节蛋白中的EGF样功能域、包含神经调节蛋白EGF样功能域的多肽、神经调节蛋白的突变体或衍生物以及其它能够激活上述受体的神经调节蛋白样的基因产物。神经调节蛋白还包括NRG-1，NRG-2，NRG-3和NRG-4蛋白、多肽、片段以及具有NRG样功能的复合物。优选的，神经调节蛋白是可以结合并激活ErbB2/ErbB4或ErbB2/ErbB3异源二聚体的蛋白或多肽。作为例子，但并非为了限制的目的，本发明的神经调节蛋白是NRG-1β2异构体的一个片段，即177-237位氨基酸片段，其中包含了EGF样功能域。该片段的氨基酸序列为：SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVMASFYKAEELYQ(SEQ ID NO:1)。本发明所用神经调节蛋白可以激活上述受体并调节它们的生物学功能，比如刺激骨骼肌细胞合成乙酰胆碱受体；促进心肌细胞的分化、存活以及DNA合成。神经调节蛋白还包括那些具有并不实质性影响生物学功能的保守性突变的神经调节蛋白突变体，如非关键区域的单个氨基酸的突变(参见Watson等人,Molecular Biology of the Gene,4th Edition,1987,The Benjamin/Cummings Pub.co.,p.224)。本发明所用神经调节蛋白可以从天然的来源分离得到，或者通过重组技术、人工合成或其它手段得到。
本文所用的“表皮生长因子样功能域”或“EGF样类似区”或“EGF样功能域”是指由neuregulin基因所编码的可以结合并激活ErbB2、ErbB3、ErbB4或其异源或同源二聚体的多肽片段，并且与下述参考文献中描述的EGF受体结合区域具有结构相似性：WO 00/64400；Holmes等，Science,256:1205-1210(1992)；美国专利5,530,109和5,716,930；Hijazi等，Int.J.Oncol.,13:1061-1067(1998)；Chang等，Nature，387:509-512(1997)；Carraway等，Nature，387:512-516(1997)；Higashiyama等，J.Biochem.,122:675-680(1997)；以及WO 97/09425。在某些实施方案中，EGF样功能域结合并激活ErbB2/ErbB4或ErbB2/ErbB3异源二聚体。在某些实施方案中，EGF样功能域包含NRG-1的受体结合区氨基酸。在某些实施方案中，EGF样功能域是指NRG-1的第177-226位、177-237位或177-240位氨基酸。在某些实施方案中，EGF样功能域包含NRG-2的受体结合区氨基酸。在某些实施方案中，EGF样功能域包含 NRG-3的受体结合区氨基酸。在某些实施方案中，EGF样功能域包含NRG-4的受体结合区氨基酸。在某些实施方案中，EGF样功能域包含美国专利5,834,229中描述的氨基酸序列：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)。
本文所用的“治疗”是指可以使不适、紊乱或疾病的症状改善或向好的方向改变的任何方式。其效果可以是预防性的，完全或部分防止某一疾病或其症状发生，也可以是治疗性的，部分或完全治愈某一疾病和/或该疾病引起的不利影响。治疗还包括此处所述组合物的任何药物用途。
本文所用的“心衰”或“心力衰竭”是指一种心脏功能的异常，在这种情况下，心脏不能按照组织代谢的需要进行供血。心力衰竭包括多种疾病状态比如充血性心力衰竭，心肌梗死，心律失常，家族性肥厚性心肌病，缺血性心脏病，特发性心肌病和心肌炎等之类的。心力衰竭可由多种因素导致，包括但不限于缺血性，先天性，风湿性，病毒性、毒性或特发性心力衰竭。慢性心脏肥大是一种显著的充血性心力衰竭前期的疾病状态，其可以引起心脏停搏。
除上下文另有说明，此处所用“蛋白”与“多肽”、“肽段”含义一致。
除上下文另有说明，此处所用“不超过”是指“小于等于”。
除另有说明，本文中“大约”或“约”为某值是指该值上下10％之内。
本文所用的“LVESVI”是指左心室收缩末期容积指数。本文所用的“LVEDVI”是指左心室舒张末期容积指数。
左心室收缩末期容积指数(LVESVI)为左心室收缩至最小时的容积/体表面积，使对于左心室收缩末期容积的评价不受身高、体重差异等因素影响。LVESVI可以通过二维(2D ECHO)和三维(3D ECHO)超声心动图、核成像、心脏计算机断层扫描和心脏磁共振成像(CMR)来测量。在健康个体中，女性LVESVI通常在8到27mL/m2范围内，男性通常在9到31mL/m2范围内。
左心室舒张末期容积指数(LVEDVI)为左心室舒张末期的容积/体表面积。LVEDVI可以通过可以通过二维(2D ECHO)和三维(3D ECHO)超声心动图、核成像、心脏计算机断层扫描和心脏磁共振成像(CMR)来测量来测量。在健康个体中，女性LVEDVI通常在29到70mL/m2范围内，男性通常在30到79mL/m2范围内。
心脏收缩功能与前负荷、后负荷、收缩性和心肌重量等因素有关。LVESVI是判断收缩功能和预后指标，在同一个体上LVEDVI和LVESVI同时发生一定幅度降低是一个清晰和明确的证据，指示患者心肌收缩力增强，心功能提高，发生逆转心室重构，能有效降低心衰患者死亡率。
本文所用的“N端脑利钠肽”或“NT-proBNP”是指无活性的N端脑利钠肽(BNP)前体片段，pro-BNP是BNP的前体，BNP是一种与激素有关的活性钠尿肽，主要由左心室壁的心肌细胞释放。在心肌壁的伸缩作用下，前激素proBNP经过蛋白酶切，分裂成BNP和无活 性的NT-proBNP。
BNP和NT-proBNP在血浆中的水平都可以用作筛选、诊断心衰，并且对建立心衰的预后非常有用，这是由于这两种标记物在病情恶化的患者身上典型升高。并且，本发明的方法包括利用BNP或NT-proBNP水平指示适合用纽兰格林治疗心衰的患者。
本文所用的“纽约心脏协会”或“NYHA”心脏功能分级是一种划分心力衰竭程度的方法。它根据患者身体活动能力的限制程度将患者分为4类。限制或症状是指正常呼吸和不同程度的呼吸困难和/或心绞痛：I，无症状并且普通的活动量不受限制，例如当走路，爬楼梯等时呼吸困难；II,轻度症状(轻度呼吸困难和/或心绞痛)并且普通的活动受到轻度的限制；III,体力活动显著受限制，甚至在少于正常活动量的情况下，例如，短距离行走(20-100m)，休息时尚感舒适；IV，严重限制活动量，即使在休息时也有症状，大多数病人卧床不起。
本发明的优点：
本发明的神经调节蛋白能改善心衰患者的心功能，特别是同时改善单个心衰患者的LVESVI和LVEDVI；同时，本发明惊讶地发现神经调节蛋白对于基线期LVESVI值高的心衰患者，特别是LVESVI≥135mL/m2的心衰患者的心功能的出乎预计的改善，其作用好于对于全部的心衰患者的心功能的改善作用。
本发明的神经调节蛋白能改善心衰患者的心功能的效果可长期维持，例如维持到给药后90天；
本发明的神经调节蛋白直接作用于心肌细胞，修复其受损的结构和功能，增强心肌收缩力，并逆转心室重构。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如教科书中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：多中心、随机、双盲、标准治疗基础上的安慰剂平行对照评价注射用重组人纽兰格林对慢性收缩性心力衰竭受试者心功能影响的III期临床试验。
本实施例试验采用多中心、随机、双盲、在标准治疗基础上的安慰剂平行对照研究，评价注射用重组人纽兰格林对男性NT-proBNP≤1700pg/ml以及女性NTproBNP≤4000pg/ml，纽约心功能分级II-III级慢性收缩性心力衰竭患者的心功能的影响，确证其疗效和安全性。
1.试验设计：
采用多中心、随机、双盲、在标准治疗基础上的安慰剂平行对照研究
试验组：注射用重组人纽兰格林+标准基础治疗药物(β受体阻滞剂、ACEI/ARB/ARNI、醛固酮受体拮抗剂等)。
安慰剂组：安慰剂+标准基础治疗药物(β受体阻滞剂、ACEI/ARB/ARNI、醛固酮受体拮抗剂等)。
2.主要入选标准
2.1年龄在18-75岁，性别不限；
2.2明确诊断心力衰竭3个月及以上，目前病情稳定，NYHA II-III级，左心室射血分数(LVEF)≤40％；
2.3男性NT-proBNP≤1700pg/ml，女性NT-proBNP≤4000pg/ml；
2.4接受心衰标准基础治疗药物满3个月，已达目标剂量或最大耐受剂量1个月以上，或1个月内未改变剂量；
2.5理解并签署知情同意书。
3.试验药物：
3.1受试药物
名称：注射用重组人纽兰格林
规格：Neucardin，61个氨基酸构成Neuregulin-1β2异构体的EGF类似功能域，分子量为7054Dal(1μg＝0.14nmol)；250μg/支。
剂型：粉针剂
给药途径：静脉滴注
外观：冻干块状物或粉末状
3.2安慰剂
名称：注射用重组人纽兰格林冻干剂的赋形剂
规格：Neucardin的赋形剂(250μg/支，不含重组人纽兰格林蛋白活性成分)
剂型：粉针剂
给药途径：静脉滴注
外观：冻干块状物或粉末状
颜色：白色或类白色
4.给药途径，用量及疗程见表1：
表1.给药途径，用量及疗程
5.数据采集：在筛选期、给药30天、90天进行有效性安全性评估。
6.结果：
本实施例在全中国多家临床研究中心同期进行，实际入组154例，纽兰格林试验组78例，安慰剂组组76例，试验最终共147例(试验组73例，安慰剂组组74例)获得主要终点指标。
6.1 LVESVI
根据获得的30天数据显示，LVESVI缩小的患者在纽兰格林实验组中占63％(见图1)，30天较基线LVESVI减少人数比例亦高于安慰剂组。
将给药后30天LVESVI较基线改善值分层(大于等于5、10、15、20、25、30、35、40ml/m2)，分别计算纽兰格林组与安慰剂组在各层级水平的改善率。LVESVI较基线减少大于等于5、10、15、20、25、30、35、40ml/m2，纽兰格林组对应改善率分别为45.2％、34.2％、23.3％、17.8％、15.1％、8.2％、5.5％、2.7％；安慰剂组对应改善率分别为：52.7％、31.1％、16.2％、5.4％、2.7％、2.7％、2.7％、2.7％。相对安慰剂组，随着改善幅度的递增，纽兰格林组中改善人数占比与安慰剂组之间出现显著差异，提示纽兰格林对LVESVI改善效果优于安慰剂，当LVESVI改善大于等于20和25ml/m2时，两组间改善率差异有统计学意义(P<0.05，见图2)。
此外，通过分析受试者入组前1个月内稳定期的两次CMR检测结果，在现有标准治疗条件下，未经试验药物干预，1个月内出现LVESVI减小超过25ml/m2以上的患者的自然发生比例为2.58％，与用药后1个月内安慰剂组中改善超过25ml/m2的比例接近(2.7％)，说明一个月内LVESVI改善超过25ml/m2的改善率数据稳定，而纽兰格林组在一个月内达到这一改善程度的改善率15.1％，显著高于自然发生的水平。综上，显示用药后能显著提高受试者心功能大幅改善率。
而通过30天心功能恶化在纽兰格林试验组和安慰剂组间差异分析显示(见表2和图3)，纽兰格林试验组LVESVI增加人数比例低于安慰剂组，与上LVESVI减少改善心功能呈现一致趋势，表明纽兰格林能防止受试者心功能恶化。
表2. 30天较基线LVESVI增加大于等于5、10、15、20、25、30ml/m2(FAS)
注：N＝组内获得LVESVI指标的受试者数量；n＝特定类别数量
纽兰格林组在用药后30天时测量心功能，相较给药前LVESVI改善5.62ml/m2，改善具有统计显著意义(P＝0.0137)，并且改善效果可以一直维持到90天测量时(P＝0.0128)；而安慰剂组在用药后30天和90天时心功能与给药前比较均未体现出统计显著的差异(P大于0.05)(见表3和图4)。
表3. 30天、90天ΔLVESVI
6.2 LVEDVI
根据获得的30天LVEDVI数据显示，30天较基线LVEDVI减少人数比例高于安慰剂组。给药后30天LVEDVI较基线减少大于等于5、10、15、20、25、30、35、40ml/m2，纽兰格林组对应改善率分别为43.8％、30.1％、21.9％、17.8％、16.4％、13.7％、6.8％和5.5％；安慰剂组对应改善率分别为：44.6％、29.7％、14.9％、12.2％、6.8％、4.1％、4.1％和2.7％。
尤其是LVEDVI减少等于或大于30ml/m2时，纽兰格林试验组为10人，改善率13.7％，安慰剂组为3人，改善率4.1％，p值0.046(见表4和图5)，纽兰格林试验组人数比例显著高于安慰剂组，差异有统计学意义。显示用药后能显著提高受试者心功能大幅改善率。
表4. 30天较基线LVEDVI减少大于等于5、10、15、20、25、30、35、40ml/m2(FAS)
注：N＝组内获得LVESVI指标受试者数量；n＝特定类别数量
而通过30天心功能恶化在纽兰格林试验组和安慰剂组差异分析显示(见表5和图6)，纽兰格林试验组LVEDVI增加人数比例低于安慰剂组，与上述LVEDVI减少改善心功能的分析一致，表明纽兰格林能防止受试者心功能恶化。
表5. 30天较基线LVEDVI的增加大于等于5、10、15、20、25、30ml/m2(FAS)
注：N＝组内获得LVESVI指标的受试者数量；n＝特定类别数量
6.3 LVESVI和LVEDVI
根据获得的受试者个体LVESVI和LVEDVI数据显示，给药后30天单个个体的LVESVI和LVEDVI较基线同时减少大于等于5、10、15、20、25、30、35、40ml/m2，纽兰格林组对应改善率分别为37.0％、23.3％、19.2％、16.4％、12.3％、6.8％、4.1％和1.4％；安慰剂组对应改善率分别为：39.2％、20.3％、12.2％、2.7％、2.7％、2.7％、2.7％和1.4％。受试者个体LVESV与LVEDV同时得到改善，尤其是LVESVI和LVEDV减同时减少20ml/m2时，纽兰格林试验组为12人，改善率16.4％，安慰剂组为2人，改善率2.7％，p值0.0048，(见表6和图7)，差异有统计学意义，表明纽兰格林能改善心功能，大幅逆转心室重构。
表6. 30天单个个体较基线LVESVI和LVEDVI同时减少大于等于5、10、15、20、25、30、35、40ml/m2(FAS)
注：N＝组内获得LVESVI指标的受试者数量；n＝特定类别数量
而通过30天心功能恶化在纽兰格林试验组和安慰剂组差异分析显示(见表7)，纽兰格林试验组单个个体的LVESVI和LVEDVI同时增加人数比例低于安慰剂组，与上述LVESVI和LVEDVI同时减少改善心功能的分析一致，表明纽兰格林能防止受试者心功能恶化。
表7. 30天较基线LVESVI和LVEDVI同时增加大于等于5、10、15、20、25、30ml/m2(FAS)
注：N＝组内获得LVESVI指标的受试者数量；n＝特定类别数量
实施例2.心功能改善效果在富集亚组人群中的研究-1
通过统计分析实施例1的试验结果，本发明人在本实施例中研究了纽兰格林在富集人群中改善LVESVI(超过13mL/m2)的应答率。这里的富集人群是指基线期LVESVI≥135mL/m2的患者，其所占所有受试者人群比例约为41％。这部分患者一般患有严重的心力衰竭，而且心室重构严重。
结果出乎意料地发现(如图8所示)：纽兰格林对富集亚组人群(基线期LVESVI≥135mL/m2，占受试者人群比例约为41％)心功能改善效果更好。
纽兰格林用药组对富集亚组人群LVESVI大幅改善(LVESVI降低13mL/m2以上)的应答率达50％，并显著高于安慰剂组。
以上结果表明，基线LVESVI越大，表明心脏越大，纽兰格林对大心脏治疗效果越好。
实施例3.心功能改善效果在富集亚组人群中的研究-2
通过统计分析实施例1的试验结果，本发明人在本实施例研究了纽兰格林在富集人群病人个体中LVESVI及LVEDVI同时发生改善(均超过20mL/m2)的应答率。
结果出乎意料地发现(如图9所示)：富集人群(基线期LVESVI≥135mL/m2)中：纽卡定用药组病人个体同时发生LVESVI及LVEDVI大幅改善(两项指标同时降低20mL/m2以上)的应答率显著高于安慰剂组。
同时，通过比较全人群和富集人群(基线期LVESVI≥135mL/m2)的纽卡定用药组和安慰剂组中病人个体同时发生LVESVI及LVEDVI大幅改善(两项指标同时降低20mL/m2以上)的应答率，本发明惊讶地发现，尽管在全人群和富集人群中纽卡定用药组病人个体同时发生LVESVI及LVEDVI大幅改善都显著高于安慰剂组，但富集人群中的纽卡定用药组比全人群的纽卡定用药组LVESVI及LVEDVI大幅改善(两项指标同时降低20mL/m2以上)的应答率更好。如图10所示。
本发明进一步统计了全人群和富集人群中施用纽卡定或者安慰剂后30日LVESVI或者LVEDVI相对于基线的改善均值。同样惊讶地发现，尽管在全人群和富集人群中纽卡定用药组病人中LVESVI或者LVEDVI相对于基线的改善均值都好于安慰剂组，但富集人群中的纽卡定用药组比全人群的纽卡定用药组LVESVI或者LVEDVI相对于基线的改善均值更好。如图11a,11b所示。这些结果都提示纽卡定对于这部分富集人群的心功能改善的作用更好，进而对于这部分富集人群在预防、治疗心衰或者延迟心衰发病方面更有效。
因此，纽兰格林对富集人群(基线期LVESVI≥135mL/m2)具有更好药效：给药组LVESVI改善大于13mL/m2的应答率达50％，具有统计学显著性；受试者个体LVESVI及LVEDVI同时改善大于20mL/m2的应答率达26.5％(安慰剂为0％，具有统计学显著性)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (44)

  1. 神经调节蛋白或其功能片段，或编码神经调节蛋白或其功能片段的核酸，或提高神经调节蛋白在人体内的产量和/或功能的物质在制备预防、治疗心衰患者或延迟心衰患者发病的药物中的用途，所述药物能改善心衰患者的心功能。
  2. 神经调节蛋白在制备预防、治疗心衰患者，延迟心衰患者发病，或者改善心衰患者的心功能的药物中的用途。
  3. 如权利要求1或2所述的用途，其特征在于，所述心衰患者是心室重构严重人群。
  4. 如权利要求1-3中任一项所述的用途，其特征在于，所述心衰患者在给药前的基线期LVESVI≥100mL/m2，或≥110mL/m2，或≥120mL/m2，或≥130mL/m2，或≥135mL/m2，或≥140mL/m2，或≥145mL/m2，或≥150mL/m2，或≥155mL/m2，或≥160mL/m2，或≥165mL/m2，或≥170mL/m2；优选≥135mL/m2；
    或者，所述心衰患者在给药前的基线期LVESVI在100-350mL/m2；110-350mL/m2；120-350mL/m2；130-350mL/m2；135-350mL/m2；优选135-350mL/m2。
  5. 如权利要求1-4中任一项所述的用途，其特征在于，所述心衰患者是慢性心衰患者。
  6. 如权利要求1-5中任一项所述的用途，其特征在于，所述心衰患者通过纽约心脏协会(NYHA)心功能分级为NYHA II或III。
  7. 如权利要求1-6中任一项所述的用途，其特征在于，所述心衰患者血浆中NT-proBNP水平不超过4000pg/ml。
  8. 如权利要求1-7中任一项所述的用途，其特征在于，所述心衰患者中，男性患者的血浆中NT-proBNP水平不超过1700pg/ml；女性患者的血浆中NT-proBNP水平不超过4000pg/ml。
  9. 如权利要求1-8中任一项所述的方法，其特征在于，所述改善心衰患者的心功能是指改善LVESVI和/或LVEDVI。
  10. 如权利要求1-9中任一项所述的用途，其特征在于，所述心衰患者在给药后LVESVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
  11. 如权利要求1-10中任一项所述的用途，其特征在于，所述心衰患者在给药后
    LVEDVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
  12. 如权利要求1-11中任一项所述的用途，其特征在于，所述改善心衰患者的心功能是同时改善单个心衰患者的LVESVI和LVEDVI。
  13. 如权利要求12所述的用途，其特征在于，所述单个心衰患者在给药后LVESVI和LVEDVI同时降低等于或大于20或25mL/m2。
  14. 如权利要求1-13中任一项所述的用途，其特征在于，所述心衰患者给药后逆转心室重构。
  15. 如权利要求1-14中任一项所述的用途，其特征在于，所述神经调节蛋白包含神经调节蛋白1(NRG-1)，神经调节蛋白2(NRG-2)，神经调节蛋白3(NRG-3)，和神经调节蛋白 4(NRG-4)。
  16. 如权利要求1-14中任一项所述的用途，其特征在于，所述神经调节蛋白包含神经调节蛋白1(NRG-1)或者NRG-1的EGF样类似区。
  17. 如权利要求1-14中任一项所述的用途，其特征在于，所述神经调节蛋白是氨基酸序列如SEQ ID NO:1所示的蛋白。
  18. 一种预防、治疗心衰患者或延迟心衰患者发病的方法，包括对需要的患者施用有效量的神经调节蛋白或其功能片段，或编码神经调节蛋白或其功能片段的核酸，或提高神经调节蛋白产量和/或功能的物质，所述方法能改善心衰患者的心功能。
  19. 一种预防、治疗心衰患者，延迟心衰患者发病或者改善心衰患者心功能的方法，包括对需要的患者施用有效量的神经调节蛋白。
  20. 如权利要求18或19所述的用途，其特征在于，所述心衰患者是心室重构严重人群。
  21. 如权利要求18-20任一项所述的方法，其特征在于，所述心衰患者在给药前的基线期LVESVI≥100mL/m2，或≥110mL/m2，或≥120mL/m2，或≥130mL/m2，或≥135mL/m2，或≥140mL/m2，或≥145mL/m2，或≥150mL/m2，或≥155mL/m2，或≥160mL/m2，或≥165mL/m2，或≥170mL/m2；优选≥135mL/m2；
    或者，所述心衰患者在给药前的基线期LVESVI在100-350mL/m2；110-350mL/m2；120-350mL/m2；130-350mL/m2；135-350mL/m2；优选135-350mL/m2。
  22. 如权利要求18-21中任一项所述的方法，其特征在于，所述心衰患者是慢性心衰患者。
  23. 如权利要求18-22中任一项所述的方法，其特征在于，所述心衰患者通过纽约心脏协会(NYHA)心功能分级为NYHA II或III。
  24. 如权利要求18-23中任一项所述的方法，其特征在于，所述心衰患者血浆中NT-proBNP水平不超过4000pg/ml。
  25. 如权利要求18-24中任一项所述的方法，其特征在于，所述心衰患者中，男性患者的血浆中NT-proBNP水平不超过1700pg/ml；女性患者的血浆中NT-proBNP水平不超过4000pg/ml。
  26. 如权利要求18-25中任一项所述的方法，其特征在于，所述改善心衰患者的心功能是指改善LVESVI和/或LVEDVI。
  27. 如权利要求18-26中任一项所述的方法，其特征在于，所述心衰患者在给药后LVESVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
  28. 如权利要求18-27中任一项所述的方法，其特征在于，所述心衰患者在给药后LVEDVI降低等于或大于10mL/m2；优选等于或大于20mL/m2。
  29. 如权利要求18-28中任一项所述的方法，其特征在于，所述改善心衰患者的心功能是同时改善单个心衰患者的LVESVI和LVEDVI。
  30. 如权利要求29所述的方法，其特征在于，所述单个心衰患者在给药后LVESVI和LVEDVI同时降低等于或大于20或25mL/m2。
  31. 如权利要求18-30中任一项所述的用途，其特征在于，所述心衰患者发生逆转心室重构。
  32. 如权利要求18-31中任一项所述的方法，其特征在于，所述神经调节蛋白包含神经调节蛋白1(NRG-1)，神经调节蛋白2(NRG-2)，神经调节蛋白3(NRG-3)，和神经调节蛋白4(NRG-4)。
  33. 如权利要求18-31中任一项所述的方法，其特征在于，所述神经调节蛋白包含神经调节蛋白1(NRG-1)或者NRG-1的EGF样类似区。
  34. 如权利要求18-31中任一项所述的方法，其特征在于，所述神经调节蛋白是氨基酸序列如SEQ ID NO:1所示的蛋白。
  35. 如权利要求18-34中任一项所述的方法，其特征在于，所述方法包括将神经调节蛋白通过导入疗程施用于患者。
  36. 如权利要求35所述的方法，其特征在于，所述导入疗程给药方案包括连续施用该药物组分至少3、5、7或10天。
  37. 如权利要求35或36所述的方法，其特征在于，所述方法包括对病人进行至少3、6或12个月的维持疗程。
  38. 如权利要求37所述的方法，其特征在于，所述维持疗程包括每3、5、7或10天施用该药物。
  39. 如权利要求18-38中任一项所述的方法，其特征在于，所述方法还包括在对需要预防、治疗或延迟心力衰竭的患者给药前评估所述患者是否适合接受神经调节蛋白治疗的步骤。
  40. 如权利要求39所述的方法，其特征在于，评估所述患者是否适合接受神经调节蛋白治疗的步骤包括对心衰患者作NYHA心脏功能评级。
  41. 如权利要求40所述的方法，其特征在于，NYHA心脏功能评级为NYHA II级或NYHA III级的患者被评估为适合接受神经调节蛋白治疗。
  42. 如权利要求39-41中任一项所述的方法，其特征在于，评估所述患者是否适合接受神经调节蛋白治疗的步骤还包括检测心衰患者的血浆NT-proBNP。
  43. 如权利要求42所述的方法，其特征在于，所述血浆NT-proBNP水平不超过4000pg/ml。
  44. 如权利要求42或43所述的方法，其特征在于，所述男性心衰患者的血浆NT-proBNP水平不超过1700pg/ml；所述女性心衰患者的血浆NT-proBNP水平不超过4000pg/ml。
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