Pharmaceutical composition for treatment of hypertrophic cardiomyopathy and treatment method using same composition
The present invention relates to a pharmaceutical composition comprising S(−)-cibenzoline or a pharmaceutically acceptable salt thereof as an active ingredient for treatment of hypertrophic cardiomyopathy, and a method for treatment of hypertrophic cardiomyopathy by using same.
1 . A method for treating hypertrophic cardiomyopathy comprising:
administering to a subject in need thereof a composition comprising a therapeutically effective amount of S(−)-cibenzoline or a pharmaceutically acceptable salt of S(−)-cibenzoline,
wherein the S(−)-cibenzoline or the pharmaceutically acceptable salt of S(−)-cibenzoline is a stereochemically pure compound with a purity of 85% ee or higher.
2 . The method of claim 1 , wherein the pharmaceutically acceptable salt thereof is selected from among salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene1-carboxylic acid, gluco-heptonic acid, 4,4-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid, trimethyl-acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid, dibenzoyl-tartaric acid, 2,3-dibenzoyl-tartaric acid, O,O-dibenzoyl-tartaric acid monohydrate, O,O-dibenzoyl-tartaric acid mono(dimethylamide), di-p-toluoyl-tartaric acid monohydrate, O,O-di-p-toluoyl-tartaric acid, menthyloxyacetic acid, α-methoxy-α-trifluoromethylphenylacetic acid, 5-oxo-2-tetrahydrofurancarboxylic acid, N-(1-phenylethyl)phthalamic acid, 2-phenylpropionic acid, pyroglutamic acid, quinic acid, aspartic acid, 1,4-benzodioxane-2-carboxylic acid N,N-bis[1-phenylethyl]phthalamic acid, 3-bromocamphor-10-sulfonic acid hydrate, camphanic acid, muconic acid, sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions.
3 . The method of claim 1 , wherein the pharmaceutical composition contains the S(−)-cibenzoline or the pharmaceutically acceptable salt of S(−)-cibenzoline at a total daily dose of 200 mg, 300 mg, 400 mg or 600 mg.
4 . The method of claim 1 , wherein the pharmaceutical composition is administered once or twice a day.
5 . The method of claim 1 , wherein the pharmaceutical composition is administered at 300 mg once a day, 200 mg once a day, 300 mg twice a day, or 200 mg twice a day.
6 . The method of claim 1 , wherein the hypertrophic cardiomyopathy is hypertrophic obstructive cardiomyopathy (HOCM).
7 . The method of claim 1 , wherein the pharmaceutical composition has one or more of the following characteristics:
i) the Cmax of the composition is about 200 ng/ml to about 700 ng/ml;
ii) the AUC of the composition is about 2,000 ng·hr/mL to about 15,700 ng·hr/mL; or
iii) the minimum plasma concentration of S(−)-cibenzoline of the composition is 160 ng/ml or more.
8 . The method of claim 1 , wherein a minimum plasma concentration of the pharmaceutical composition is 160 ng/ml or more.
9 . The method of claim 1 , wherein the hypertrophic cardiomyopathy is hypertrophic obstructive cardiomyopathy (HOCM) having one or more of the following characteristics:
a) a maximal left ventricular wall thickness of 15 mm or more (13 mm or more if there is a family history);
b) a left ventricular outflow tract (LVOT) gradient of 30 mmHg or more at rest, or an LVOT gradient of 50 mmHg or more after provocation (including Valsalva maneuver, standing, post-exercise, etc.); or
c) a left ventricular ejection fraction (LVEF) of 55% or more.
10 . The method of claim 1 , wherein the pharmaceutical composition is not administered to hypertrophic cardiomyopathy patients having one or more of the following characteristics:
1) patients with a history of heart disease, including one or more of known infiltrative, hereditary or storage disorders causing cardiac hypertrophy that mimic HCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy;
2) patients with a history of persistent atrial fibrillation before screening or baseline;
3) patients who underwent implantable cardioverter-defibrillator (ICD) implantation within 2 months before screening or who planned to undergo ICD implantation during a clinical trial period;
4) patients with symptoms of systolic heart failure with an ejection fraction <55% or New York Heart Association (NYHA) class IV heart failure;
5) patients with QTcF>480 msec at screening or baseline;
6) patients with systolic BP<90 mmHg or >160 mmHg and/or diastolic BP>100 mmHg or <60 mmHg at screening or baseline;
7) patients who received vardenafil hydrochloride, moxifloxacin hydrochloride, toremifene citrate, fingolimod hydrochloride or eliglustat tartrate, or other agents known to prolong QT/QTcF, within a period of at least 7 days or five times the half-life (whichever is longer) before screening;
8) patients who received disopyramide or ranolazine within a period of at least 7 days or five times the half-life (whichever is longer) before screening;
9) patients who received antiarrhythmic agents other than beta-blockers within a period of at least 7 days or five times the half-life (whichever is longer) before screening (except cases where there is no change in doses/drugs within a period of at least 7 days or five times the half-life (whichever is longer) before screening for patients on beta-blockers in the opinion of a physician);
10) patients who received inotropic agents, angiotensin converting enzyme I, angiotensin II receptor blockers (ARBs), nitrate drugs, PDE inhibitors, anticholinergics, xanthine derivatives, etc. within a period of at least 7 days or five times the half-life (whichever is longer) before screening; or
11) patients who previously received doxorubicin as a cardiotoxic agent.
11 . The method of claim 1 , wherein the pharmaceutical composition improves a left ventricular outflow tract (LVOT) gradient value.
12 . The method of claim 11 , wherein the improvement is a change (or decrease) of at least 1%, 2%, 5%, or 10% relative to an initial measured value.
13 . The method of claim 1 , wherein the pharmaceutical composition is co-administered with other therapeutic agent for heart disease.
14 . The method of claim 13 , wherein the other therapeutic agent for heart disease is selected from the group consisting of beta blockers, calcium channel blockers, and antiarrhythmic drugs.