METHOD FOR PREVENTING, TREATING OR DELAYING HEART FAILURE BY USING NEUREGULIN, AND COMPOSITION

Abstract

The present invention provides an application of neuregulin protein in the preparation of drugs for preventing, treating or delaying human heart failure, and a use method of the drugs for preventing, treating or delaying human heart failure. The method comprises: testing a patient first before treatment, the testing comprises detecting the plasma level of NT-proBNP or BNP; and then providing appropriate treatment on the basis of the test result. When the test result is within an optimal treatment range, the patient is suitable for the treatment of heart failure by administering an effective dose of neuregulin.

Claims

1. Use of NRG in the manufacture of a medicament for the treatment of heart failure (HF), wherein a patient with the heart failure is a female HF patient whose pre-treatment plasma level of NT-proBNP is not more than 3000 fmol/ml.

2. The use of claim 1, wherein the NRG is NRG-1.

3. The use of claim 1, wherein the NRG contains an EGF-like domain of NRG-1.

4. The use of claim 1, wherein the NRG contains an amino acid sequence of SEQ ID NO:1.

5. A method of screening a HF patient suitable for treatment with Neuregulin, comprising performing a pre-treatment diagnostic test, and determining the eligibility of the patient for Neuregulin treatment according to the test results.

6. The method of claim 5, wherein the diagnostic test is a test for the plasma level of NT-proBNP or BNP.

7. The method of claim 6, when a female HF patient has a pre-treatment plasma level of NT-proBNP not more than 3000 fmol/ml, the diagnostic test results indicate suitability for treatment with Neuregulin.

8. A diagnostic kit used for screening a HF patient suitable for treatment with Neuregulin, the diagnostic kit contains immunoassay reagents for measuring the NT-proBNP plasma level in HF patients.

9. The diagnostic kit of claim 8, when a female HF patient has a pre-treatment plasma level of NT-proBNP not more than 3000 fmol/ml, the diagnostic test results indicate suitability for treatment with Neuregulin.

10. A kit for the treatment of heart failure, comprising the diagnostic kit of claim 8 and an effective dose of NRG.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0052] Embodiment 1: A Randomized, Double-Blinded, Multi-Center, Placebo Controlled Survival Study of Recombinant Human Neuregulin in Patients with Chronic Heart Failure Based on Standard Treatment (Study 209)

[0053] In order to evaluate the efficacy of Recombinant Human Neuregulin (rhNRG-1) for injection in the treatment of chronic heart failure, a phase II, double-blinded, multi-center, placebo controlled, standard treatment based study was carried out in multiple clinical centers in China. A total of 351 patients with NYHA Class III or Class IV chronic heart failure were enrolled and randomized to Placebo Group or rhNRG-1 Group (0.6 μg/kg). There was no significant difference between the groups in terms of demographics and background treatment. The patients were admitted to hospital for administration of the drug for 10 consecutive days as scheduled and discharged on Day 11. From the 3rd week to the 25th week, the patients were administered a weekly dose in outpatient department. Blood samples were collected from the patients before treatment and after each administration. Determination of NT-proBNP level in plasma by a core laboratory (with reagent kit from Biomedica). In Week 52 of the study, information on the ‘patients’ survival was collected.

Investigational Product:

[0054] Specification: rhNRG-1, 61 amino acid polypeptide comprises the EGF-like domain of Neuregulin-1 β2 isoform, with the molecular weight of 7054 Da (1 pg=0.14 nmol).

Placebo:

[0055] Specification: Excipient for rhNRG-1 (250 pg/vial without active recombinant human neuregulin-1 protein).

Dosage Regimen:

[0056]

TABLE-US-00001 1-10 days 3-25 weeks Dose 0.6 μg/kg/day rhNRG-1 or 0.8 μg/day rhNRG-1 or placebo placebo Route of Intravenous drop Intravenous infusion administration Treatment 10 hours/day, for 10 weekly 10-minute infusion course consecutive days

[0057] Criteria for participation in the trial included patients with CHF (NYHA class III or IV between the ages of 18 and 65 years old, LVEF≤40%, in relatively stable clinical condition (including clinical signs, symptoms and accepted standard treatment for CHF at the target dose or maximum tolerance dose for over 1 month). Major exclusion criteria included acute myocardial infarction, hypertrophic cardiomyopathy, constrictive pericarditis, significant valve disease or congenital heart disease, severe pulmonary hypertension, systolic blood pressure <90 mmHg or >160 mmHg, severe ventricular arrhythmia, cardiac surgery or a cerebrovascular event within the previous six months, claustrophobia or pregnant female subjects. All patients provided witnessed written consent.

Embodiment 2: A Multi-center, Randomized, Double-blinded, Placebo Controlled Survival Study of Recombinant Human Neuregulin in Patients with Chronic Heart Failure Based on Standard Treatment (Study 301)

[0058] In order to evaluate the efficacy of Recombinant Human Neuregulin (rhNRG-1) for Injection in the treatment of chronic heart failure, a phase III, double-blinded, multi-center, placebo controlled, standard treatment based study was carried out in multiple clinical centers in China. A total of 331 patients with NYHA Class III or Class IV chronic heart failure were enrolled and randomized to Placebo Group or rhNRG-1 Group (0.6 μg/kg) or rhNRG-1 Group (1.0 μg/kg). There was no significant difference between the groups in terms of demographics and background treatment. The patients were admitted to hospital for administration of the drug for 10 consecutive days as scheduled and discharged on Day 11. From the 3rd week to the 25th week, the patients were administered a weekly dose in outpatient department. Blood samples were collected from the patients before treatment and after each administration. Determination of NT-proBNP level in plasma by a core laboratory (with reagent kit from Biomedica). In Week 52 of the study, information on the patients' survival was collected.

Investigational Product:

[0059] Specification: rhNRG-1, 61 amino acid polypeptide comprises the EGF-like domain of Neuregulin-1 β2 isoform, with the molecular weight of 7054 Dal (1 pg=0.14 nmol).

Placebo:

[0060] Specification: Excipient for rhNRG-1 (250 pg/vial without active recombinant human neuregulin-1 protein).

Dosage Regimen:

[0061]

TABLE-US-00002 1-10 days 3-25 weeks Dose 0.6 μg/kg/day rhNRGl or 0.8 μg/kg/day rhNRG-1 or 1.0 μg/kg/day rhNRG-1 placebo or placebo Route of Intravenous drip Intravenous infusion administration Treatment 10 hours/day, for 10 weekly 10-minute infusion course consecutive days

[0062] Criteria for participation in the trial included patients with CHF (NYHA class III or IV) between the ages of 18 and 80 years old, LVEF≤40%, in relatively stable clinical condition (including clinical signs, symptoms and accepted standard treatment for CHF at the target dose or maximum tolerance dose for over 1 month). Major exclusion criteria included acute myocardial infarction, hypertrophic cardiomyopathy, constrictive pericarditis, significant valve disease or congenital heart disease, severe pulmonary hypertension, systolic blood pressure <90 mmHg or >160 mmHg, severe ventricular arrhythmia, cardiac surgery or a cerebrovascular event within the previous six months, claustrophobia or pregnant female subjects. All patients provided witnessed written consent.

Embodiment 3: A Multi-center, Randomized, Double-blind, Placebo Controlled Survival Study of Recombinant Human Neuregulin in Patients with Chronic Heart Failure Based on Standard Treatment (Study 305)

[0063] In order to evaluate the efficacy of Recombinant Human Neuregulin (rhNRG-1) for Injection in the treatment of chronic heart failure, a double-blind, multi-center, placebo controlled, standard treatment based study was carried out in multiple clinical centers in China. A total of 679 patients with NYHA Class II or Class III chronic heart failure were enrolled and randomized to Placebo Group or rhNRG-1 Group (0.6 μg/kg). There was no significant difference between the groups in terms of demographics and background treatment. The patients were admitted to hospital for administration of the drug for 10 consecutive days as scheduled and discharged on Day 11. From the 3rd week to the 25th week, the patients were administered a weekly dose in outpatient department. Blood samples were collected from the patients before treatment and after each administration. Determination of NT-proBNP level in plasma by a core laboratory (with reagent kit from Biomedica). In Week 52 of the study, information on the patients' survival was collected.

Investigational Product:

[0064] Specification: rhNRG-1, 61 amino acid polypeptide comprises the EGF-like domain of Neuregulin-1 β2 isoform, with the molecular weight of 7054 Dal (1 pg=0.14 nmol). Placebo:

[0065] Specification: Excipient for rhNRG-1 (250 pg/vial without active recombinant human neuregulin-1 protein).

Dosage Regimen:

[0066]

TABLE-US-00003 1-10 days 3-25 weeks Dose 0.6 μg/kg/day rhNRG-1 or 0.8 μg/kg/day rhNRG-1 or placebo placebo Route of Intravenous drip Intravenous infusion administration Treatment 10 hours/day, for 10 weekly 10-minute infusion course consecutive days

[0067] Inclusion criteria for the clinical study: chronic HF patients (NYHA Functional Class II or Class III) aged 18-75 yo, LVEF≤40%, clinical symptoms stable (including clinical symptoms, physical signs), having received HF basic standard of care at target dose level or maximum tolerated dose for more than 1 month). Exclusion criteria: acute myocardial infarction, hypertrophic cardiomyopathy, stenosing pericarditis, notable valvular pathological changes or congenital cardiac diseases, severe pulmonary artery hypertension, systolic pressure <90 mmHg or >160 mmHg, serious ventricular arrhythmia, patients received cardiac surgical treatment or experienced cerebrovascular accident in the 6 months prior to the study, claustrophobia or pregnant females. All patients need to understand and sign the Informed Consent Form.

[0068] The applicant performed statistical analyses of the data from the three separate clinical studies. Results from the analyses of pooled data from three separate clinical studies in all female subjects (mild, moderate, severe patients in NYHA Class II—IV): females in treatment groups achieved statistically significant survival benefits (P=0.016) vs. Patients in standard of treatment-based placebo-controlled group. In the study period, subjects' all-cause mortality decreased by 50% or above. In each of the separate studies, all females in treatment groups achieved survival benefits, showing a trend in agreement with that from the analysis of pooled data from the three studies.

[0069] Results from analysis of pooled data: generally speaking, during the study period, the lower the subjects' baseline NT-proBNP level, the greater their survival benefits (relative decrease of all-cause mortality); of the female subjects who had NT-proBNP level not more than 3000 fmol/ml at baseline, those in treatment groups had a mortality rate of 0%; in contrast, the all-cause mortality of subjects in standard of treatment-based placebo-controlled group was nearly 10%; subjects in treatment groups achieved statistically very significant survival benefits (P<0.001). In all of the separate studies, female subjects showed a trend for survival benefits in agreement with that in the analysis of pooled data.

[0070] Clinical results revealed that rhNRG-1 could identify patients with mild to moderate heart failure more effectively, and this was in line with the results from studies in HF rat models induced by coarctation of aorta. It was shown when HF proceeded to a more serious stage when the heart deflects and blood pumping function collapse the expression of ErbB2 and ErbB4 receptors would decrease significantly. In light of this, at early stage of HF, i.e., before the downregulation of ErbB2/ErbB4 receptor expression, recombinant human Neuregulin can deliver more benefits to patients.

TABLE-US-00004 TABLE 1 All-cause mortality - Summary of subgroup analysis: (Pooled analysis of data from Study 209/301/305) n/N (%) Variable rhNRG-1 Placebo Overall 80/728(11.0) 77/633(12.2) Gender Male 68/560(12.1) 53/484(11.0) Female 12/168(7.1)  24/149(16.1) NYHA Class at baseline Class II 9/138(6.5) 10/137(7.3)  Class III 46/501(9.2)  59/441(13.4) Class IV  25/89(28.1)  8/55(14.5) NT-proBNP at baseline ≤1600 fmol/ml 7/349(2.0) 21/332(6.3)  1600-4000 fmol/ml 37/238(15.5) 29/190(15.3) ≥4000 fmol/ml  30/95(31.6)  22/81(27.2) Skipping  6/46(13.0)  5/30(16.7) Abbreviations: LVEF = left ventricular ejection fraction, N = total number of subjects analyzed, n = number of subjects in a specific category, NYHA = New York Heart Association

[0071] When assay results revealed that baseline NT-proBNP was ≤1600 fmol/ml, rhNRG-1 showed the potential to lower the mortality of subjects significantly (Table 1) regardless of subject's sex; however, this conclusion does not apply to the analysis of pooled data from subjects of both sexes who have higher baseline NT-proBNP. Further analysis revealed that rhNRG-1 had resulted in statistically significantly lower mortality (Table 1) in all test female subjects. It was found in Individual Studies 209, 301 and 305 that females showed the same trend, as shown in Table 2.

TABLE-US-00005 TABLE 2 All-cause mortality - Summary of subgroup analysis: Single clinical study (Analysis of Study 209/301/305) 209 301 305 n/N (%) n/N (%) n/N (%) Variable rhNRG-1 Placebo rhNRG-1 Placebo rhNRG-1 Placebo Overall 18/175 (10.3) 29/176 (16.5) 34/214 (15.9) 14/117 (12.0)  28/339 (8.3) 34/340 (10.0) Gender Male 14/142 (9.9)  18/138 (13.0) 32/168 (19.0) 10/86 (11.6) 22/250 (8.8) 25/260 (9.6)  Female  4/33 (12.1)  11/38 (28.9)  2/46 (4.35)  4/31 (12.9)  6/89 (6.7)  9/80 (11.3) Abbreviations: LVEF = left ventricular ejection fraction, N = total number of subjects analyzed, n = number of subjects in a specific category, NYHA = New York Heart Association

[0072] Baseline NT-proBNP percentiles were subjected to further subgroup analysis for female subjects since they showed better improvements in both pooled studies and individual studies. These subgroups were subjected to pooled and single analyses for patients whose NT-proBNP≤1600 fmol/ml (˜50%), NT-proBNP≤3000 fmol/ml (˜75%) and all female patients, as shown in Table 3.

[0073] Pooled analysis of the three clinical studies 209, 301 and 305 revealed that the mortality rate of females subjects was 0%, 0% and 7.1%, respectively, in the three subgroups of female subjects on rhNRG-1 treatment, i.e., Subgroup NT-proBNP≤1600, Subgroup NT-pro BNP≤3000 fmol/ml, and all female patients on the therapy. The mortality rate in the three corresponding subgroups of subjects on placebo was 8.4%, 10.4% and 16.1%, respectively; it was shown that rhNRG-1 can significantly lower mortality rate, particularly in the NT-proBNP≤3000 fmol/ml subgroup, female subjects in this subgroup account for 75% of the enrolled female subjects, as shown in Table 3.

[0074] Individual analyses of studies 209, 301 and 305 revealed that the mortality rate of female subjects in the NRG-1 Treatment Group was 0%, 0% and 0%, respectively, for NT-proBNP≤3000 fmol/ml subgroups in the studies, while the mortality rate was 21.4%, 8.3% and 6.3%, in the corresponding placebo group, as shown in Table 3.

[0075] For male patients, in NT-proBNP≤4000 fmol/ml or NT-proBNP≤3000 fmol/ml subgroups, some clinical studies showed rhNRG-1 Treatment Group had mortality rate superior to that in placebo group. More preferably, pooled analyses of male subjects whose NT-proBNP≤1600 fmol/ml in studies 209, 301 and 305 revealed that the mortality rate in rhNRG-1 Treatment Group was substantially lower than that in the Placebo group (2.6% vs. 5.6%). This decrease was in line with the comprehensive analysis of all subjects of both sexes.

TABLE-US-00006 TABLE 3 All-cause mortality - Summary of female subgroup analysis: (Pooled analysis & Individual analysis of data from Study 209/301/305) All-cause mortality Baseline NT-proBNP value-based female subgroup NT-proBNP rhNRG-1 Placebo Clinical studies (fmol/ml) n/N (%) n/N (%) 209 ≤1600 0/12 (0.0)  3/20 (15.0) ≤3000 0/16 (0.0)  6/28 (21.4) All  4/33 (12.1) 11/38 (28.9) 301 ≤1600 0/16 (0.0)  2/20 (10.0) ≤3000 0/33 (0.0) 2/24 (8.3) All 2/46 (4.3)  4/31 (12.9) 305 ≤1600 0/53 (0.0) 2/43 (4.7) ≤3000 0/69 (0.0) 4/63 (6.3) All 6/89 (6.7)  9/80 (11.3) 209, 301 & 305 ≤1600 0/81 (0.0) 7/83 (8.4) ≤3000 0/118 (0.0)  12/115 (10.4)  All 12/168 (7.1)  24/149 (16.1) 

[0076] In light of the above analyses, individual and pooled analyses of the female subjects who had NT-proBNP<3000 fmol/ml and male subjects who had NT-proBNP≤1600 fmol/ml in any of the three clinical studies were performed as shown in Table 4. For these pooled male and female subjects, the mortality improvement result in the rhNRG-1 Treatment Group was significantly superior to that in the placebo group.

TABLE-US-00007 TABLE 4 All-cause mortality - Summary of subgroup analysis: (Pooled analysis & Individual analysis of data from Study 209/301/305) All-cause mortality Female NT-proBNP ≤3000 & Male NT- proBNP ≤1600 fmol/ml rhNRG-1 Placebo Clinical studies n/N (%) n/N (%) 209  1/72 (1.4) 10/91 (11.0) 301 1/106 (0.9) 2/63 (3.2) 305 5/208 (2.4) 14/210 (6.7)  209, 301&305 7/386 (1.8) 26/364 (7.1) 

[0077] The above-listed embodiments would not limit the protection range of the study. Technicians in the art may adjust and modify this invention without deviation from the purpose and scope of the invention. Therefore, the protection range of this invention should be defined according to rights and requirements rather than by specific embodiments.