Therapeutic Dosing of a Neuregulin or a Fragment Thereof for Treatment or Prophylaxis of Heart Failure
The invention relates to treatment and prevention of heart failure in a mammal. The invention provides a dosing regimen whereby the therapeutic benefits conferred by administration of peptide comprising an epidermal growth factor-like domain, e.g., a neuregulin such as glial growth factor 2 (GGF2) or a functional fragment thereof, are maintained and/or enhanced, while concomitantly minimizing any potential side effects.
1 . A method for treating or preventing heart failure in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a peptide, wherein the peptide comprises an epidermal growth factor-like (EGF-like) domain, wherein the therapeutically effective amount is from about 0.005 mg/kg bodyweight to about 4 mg/kg bodyweight, and wherein the peptide is administered on a dosing interval of at least 24 hours.
2 . The method of claim 1 , wherein the peptide comprising an EGF-like domain is administered to the subject according to an escalating dosing regimen, said method comprising administering said peptide at a first therapeutically effective dose, and subsequently administering a second therapeutically effective dose, wherein the second dose is higher than the first dose.
3 . The method of claim 1 , wherein the therapeutically effective amount is from about 0.007 mg/kg bodyweight to about 1.5 mg/kg bodyweight.
4 . The method of claim 1 , wherein the therapeutically effective amount is selected from the group consisting of: about 0.007 mg/kg bodyweight, about 0.02 mg/kg bodyweight, about 0.06 mg/kg bodyweight, about 0.19 mg/kg bodyweight, about 0.38 mg/kg bodyweight, 0.76 mg/kg bodyweight, and about 1.51 mg/kg bodyweight.
5 . The method of claim 1 , wherein the dosing interval is at least 2 weeks.
6 . The method of claim 5 , wherein the therapeutically effective amount is about 0.35 mg/kg bodyweight to about 3.5 mg/kg bodyweight.
7 . The method of claim 2 , wherein the dosing regimen comprises the steps of:
a) administering an initial dose of the peptide in the range of about 0.005 mg/kg bodyweight to about 0.015 mg/kg bodyweight;
b) thereafter administering a second dose of the peptide that is 2-fold to 3-fold above the previous dose; and
c) repeating step b) until a maximum therapeutic dose is reached,
wherein the maximum therapeutic dose does not elicit an adverse event in the subject, and wherein the doses are administered on an interval of at least 24 hours.
8 . The method of claim 7 , wherein the maximum therapeutic dose is about 0.7 mg/kg bodyweight to about 1.5 mg/kg bodyweight.
9 . The method of claim 1 , wherein the peptide comprises glial growth factor 2 (GGF2) or a functional fragment thereof.
10 . The method of claim 9 , wherein the GGF2 or functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
11 . The method of claim 9 , wherein the heart failure is chronic heart failure.
12 . The method of claim 11 , wherein the subject has suffered from chronic heart failure for at least 1 month prior to administration of the peptide.
13 . The method of claim 9 , wherein the subject suffers from class 2, 3, or 4 heart failure prior to administration of the peptide.
14 . The method of claim 9 , wherein the subject has a left ventricular ejection fraction of 40% or less or a preserved left ventricular ejection fraction prior to administration of the peptide.
15 . The method of claim 9 , wherein the therapeutically effective amount is sufficient to increase the left ventricular ejection fraction (LVEF), decrease the end systolic volume (ESV), decrease the end diastolic volume (EDV), increase the fractional shortening (FS), decrease the number of hospitalizations, increase exercise tolerance, decrease the number of occurrences of or the severity of mitral valve regurgitation, decrease dyspnea, decrease peripheral edema, or a combination thereof, in the subject.
16 . The method of claim 15 , wherein the increase in the left ventricular ejection fraction (LVEF), the decrease in the end systolic volume (ESV), the decrease in the end diastolic volume (EDV), the increase in the fractional shortening (FS), or combination thereof occurs within 90 days of the first administration of the peptide.
17 . The method of claim 9 , wherein the peptide is administered intravenously or subcutaneously.
18 . The method of claim 9 , further comprising administering a therapeutically effective amount of a benzodiazepine.
19 .- 20 . (canceled)
21 . The method of claim 5 , wherein the dosing interval is one month, two months, three months, four months, five months, or six months.