Methods for treating hypertrophic cardiomyopathy

Abstract

Methods for treating obstructive hypertrophic cardiomyopathy are described herein. The treatment methods include the administration of a cardiac myosin inhibitor (CK-3773274, also referred to as CK-274 or aficamten) and may include titrating an administrated daily dose based on one or more components of an echocardiogram. The daily dose may be increased, maintained, decreased, or terminated, based on the echocardiogram.

1 . A method of (a) reducing resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30 mmHg, or (b) reducing post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) to less than 50 mmHg, or (c) reducing resting left ventricular outflow tract pressure gradient (LVOT-G) to less than 30 mmHg and reducing post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) to less than 50 mmHg, in a patient with obstructive hypertrophic cardiomyopathy (oHCM) comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 - 5 . (canceled) 
     
     
         6 . A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein said patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 50 mmHg prior to administering Compound 1 or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein said patient has a resting left ventricular outflow tract pressure gradient (LVOT-G) of at least 30 mmHg and less than 50 mmHg, and a post-Valsalva left ventricular outflow tract pressure gradient (LVOT-G) of at least 50 mmHg prior to administering Compound 1 or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein said patient is eligible for septal reduction therapy (SRT). 
     
     
         9 - 10 . (canceled) 
     
     
         11 . A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient with heart failure symptoms, comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein the method results in a reduction of heart failure symptoms as assessed by NYHA classification. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . A method of reducing NT-proBNP levels in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A method of reducing cardiac troponin I levels in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . A method of decreasing left ventricular wall stress in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein the patient has obstructive hypertrophic cardiomyopathy (oHCM). 
     
     
         19 . (canceled) 
     
     
         20 . A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, is selected by titrating a daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, administered to the patient. 
     
     
         21 - 25 . (canceled) 
     
     
         26 . A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising:
 administering to the patient a first daily dose of Compound 1,   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, for a first time period; and
 based on one or more components of a first echocardiogram for the patient acquired after the first time period, administering to the patient a second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, for a second time period or terminating the administering of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient. 
 
     
     
         27 . The method of  claim 26 , comprising selecting the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, based on the one or more components of the first echocardiogram. 
     
     
         28 . The method of  claim 26 , wherein the one or more components of the first echocardiogram comprises (a) a biplane LVEF, (b) a post-Valsalva LVOT-G, (c) a resting LVOT-G, (d) a biplane LVEF and a post-Valsalva LVOT-G, or (e) a biplane LVEF, a post-Valsalva LVOT-G, and a resting LVOT-G. 
     
     
         29 . The method of  claim 26 , wherein the one or more components of the first echocardiogram comprises a biplane LVEF, and the second daily dose of Compound 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, is lower than the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold. 
     
     
         30 . The method of  claim 26 , wherein the one or more components of the first echocardiogram comprises a biplane LVEF, and the administering of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient is terminated when the biplane LVEF of the first echocardiogram is below a predetermined biplane LVEF threshold. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . The method of  claim 26 , wherein the one or more components of the first echocardiogram comprises a biplane LVEF and a post-Valsalva LVOT-G, and wherein the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when either of the following conditions are met on the first echocardiogram: (1) the biplane LVEF is at or above the predetermined biplane LVEF threshold and below a second predetermined biplane LVEF threshold; or (2) the biplane LVEF is at or above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is below a second predetermined post-Valsalva LVOT-G threshold. 
     
     
         34 . The method of  claim 26 , wherein the one or more components of the first echocardiogram comprises a biplane LVEF and a post-Valsalva LVOT-G, and wherein the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is greater than the first daily dose of Compound 1 when the biplane LVEF of the first echocardiogram is above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the first echocardiogram is at or above the second predetermined post-Valsalva LVOT-G threshold. 
     
     
         35 . The method of  claim 26 , wherein the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg of Compound 1. 
     
     
         36 . The method of  claim 35 , wherein the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg or about 10 mg of Compound 1. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 26 , wherein the first time period is about 2 weeks. 
     
     
         39 . The method of  claim 26 , wherein the second time period is about 2 weeks. 
     
     
         40 . The method of  claim 26 , wherein the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient for the second time period, the method further comprising, based on one or more components of a second echocardiogram for the patient acquired after the second time period and the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, administering to the patient a third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof for a third time period or terminating the administering of Compound 1, or a pharmaceutically acceptable salt thereof to the patient. 
     
     
         41 . The method of  claim 40 , comprising selecting the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, based on the one or more components of the second echocardiogram and the second daily dose. 
     
     
         42 . The method of  claim 40 , wherein the one or more components of the second echocardiogram comprises (a) a biplane LVEF, (b) a post-Valsalva LVOT-G, (c) a resting LVOT-G, (d) a biplane LVEF and a post-Valsalva LVOT-G, or (e) a biplane LVEF, a post-Valsalva LVOT-G, and a resting LVOT-G. 
     
     
         43 . The method of  claim 40 , wherein the one or more components of the second echocardiogram comprises a biplane LVEF, and the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is lower than the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, or the administering of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient is terminated, when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold. 
     
     
         44 . The method of  claim 40 , wherein the administering of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient is terminated when the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold and the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is the same as the first daily dose of Compound 1 or lower. 
     
     
         45 . The method of  claim 40 , wherein the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is higher than the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the second echocardiogram is below the predetermined biplane LVEF threshold. 
     
     
         46 - 47 . (canceled) 
     
     
         48 . The method of  claim 40 , wherein the one or more components of the second echocardiogram comprises a biplane LVEF and a post-Valsalva LVOT-G, and wherein the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when either of the following conditions are met on the second echocardiogram: (1) the biplane LVEF is at or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold; or (2) the biplane LVEF is at or above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is below the second predetermined post-Valsalva LVOT-G threshold. 
     
     
         49 . The method of  claim 40 , wherein the one or more components of the second echocardiogram comprises a biplane LVEF and a post-Valsalva LVOT-G, and wherein the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is greater than the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when the biplane LVEF of the second echocardiogram is above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the second echocardiogram is at or above the second predetermined post-Valsalva LVOT-G threshold. 
     
     
         50 . The method of  claim 40 , wherein the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg of Compound 1, the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg or about 10 mg of Compound 1, and the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg, about 10 mg, or about 15 mg of Compound 1. 
     
     
         51 . (canceled) 
     
     
         52 . The method of  claim 40 , wherein the third time period is about 2 weeks. 
     
     
         53 . The method of  claim 40 , wherein the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient for the third time period, the method further comprising, based on one or more components of a third echocardiogram for the patient acquired after the third time period and the third daily dose of Compound, or a pharmaceutically acceptable salt thereof, administering to the patient a fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, for a fourth time period or terminating the administering of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient. 
     
     
         54 . The method of  claim 53 , comprising selecting the fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, based on the one or more components of the third echocardiogram and the third daily dose. 
     
     
         55 . The method of  claim 53 , wherein the one or more components of the third echocardiogram comprises (a) a biplane LVEF, (b) a post-Valsalva LVOT-G, (c) a resting LVOT-G, (d) a biplane LVEF and a post-Valsalva LVOT-G, or (e) a biplane LVEF, a post-Valsalva LVOT-G, and a resting LVOT-G. 
     
     
         56 . The method of  claim 53 , wherein the one or more components of the third echocardiogram comprises a biplane LVEF, and the fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is lower than the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, or the administering of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient is terminated, when the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold. 
     
     
         57 . The method of  claim 53 , wherein the administering of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient is terminated when the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold and the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, or lower. 
     
     
         58 . The method of  claim 53 , wherein:
 the fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is higher than the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold; or   the fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, and the biplane LVEF of the third echocardiogram is below the predetermined biplane LVEF threshold.   
     
     
         59 - 60 . (canceled) 
     
     
         61 . The method of  claim 53 , wherein the one or more components of the third echocardiogram comprises a biplane LVEF and a post-Valsalva LVOT-G, and wherein the fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is the same as the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when either of the following conditions are met on the third echocardiogram: (1) the biplane LVEF is at or above the predetermined biplane LVEF threshold and below the second predetermined biplane LVEF threshold; or (2) the biplane LVEF is at or above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G is below the second predetermined post-Valsalva LVOT-G threshold. 
     
     
         62 . The method of  claim 53 , wherein the one or more components of the third echocardiogram comprises a biplane LVEF and a post-Valsalva LVOT-G, and wherein the fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is greater than the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, when the biplane LVEF of the third echocardiogram is above the second predetermined biplane LVEF threshold and the post-Valsalva LVOT-G of the third echocardiogram is at or above the second predetermined post-Valsalva LVOT-G threshold. 
     
     
         63 . The method of  claim 53 , wherein the first daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg of Compound 1, the second daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg or about 10 mg of Compound 1, the third daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg, about 10 mg, or about 15 mg of Compound 1, and the fourth daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 5 mg, about 10 mg, about 15 mg, or about 20 mg of Compound 1. 
     
     
         64 . (canceled) 
     
     
         65 . The method of  claim 53 , wherein the fourth time period is about 2 weeks. 
     
     
         66 . The method of  claim 29 , wherein the predetermined biplane LVEF threshold is 50%, the second predetermined biplane LVEF threshold is 55%, and the second predetermined post-Valsalva LVOT-G threshold is 30 mmHg. 
     
     
         67 . The method of  claim 29 , wherein, prior to administration of Compound 1, or a pharmaceutically acceptable salt thereof, the patient has (i) resting LVOT-G≥50 mmHg; or (ii) resting LVOT-G≥30 mmHg and <50 mmHg with post-Valsalva LVOT-G≥50 mmHg. 
     
     
         68 . The method of  claim 29 , wherein prior to administration of Compound 1, or a pharmaceutically acceptable salt thereof, the patient has left ventricular ejection fraction (LVEF)≥60%. 
     
     
         69 . (canceled) 
     
     
         70 . The method of  claim 29 , wherein the patient is administered disopyramide or another antiarrhythmic medication during the treatment with Compound 1, or a pharmaceutically acceptable salt thereof. 
     
     
         71 . The method of  claim 29 , wherein the patient has not been treated with disopyramide or an antiarrhythmic drug that has negative inotropic activity within 4 weeks prior to treatment with Compound 1, or a pharmaceutically acceptable salt thereof. 
     
     
         72 . (canceled) 
     
     
         73 . The method of  claim 29 , wherein the patient is a CYP2D6 poor metabolizer. 
     
     
         74 - 75 . (canceled) 
     
     
         76 . The method of  claim 29 , wherein the method does not include taking a blood sample of the patient. 
     
     
         77 . (canceled) 
     
     
         78 . The method of  claim 29 , wherein the patient is administered a beta-blocker during the treatment with Compound 1, or a pharmaceutically acceptable salt thereof. 
     
     
         79 . The method of  claim 29 , wherein the method results in one or more of the following: improvement in mitral regurgitation, improvement in cardiac relaxation, beneficial cardiac remodeling, reverse cardiac remodeling, beneficial cardiac structural remodeling, beneficial cardiac functional remodeling, reversal of adverse cardiac remodeling, reduction in mean left ventricular mass index (LVMI), improvement in left ventricular (LV) filling pressures, reduction in left atrial volume index (LAVI), reduction in the categorical assessment of systolic anterior motion of the mitral valve leaflet, reduction in systolic anterior motion of the mitral valve leaflet, reduction in the frequency of eccentric mitral regurgitation, reduction in mitral regurgitation, reduction in lateral E/e′, reduction in lateral E/E, reduction in brain natriuretic peptide (BNP) and reduction in N-terminal prohormone of brain natriuretic peptide (NT-proBNP); or 
       wherein the method results in one or more of the following: improvement in exercise capacity, improvement in peak oxygen uptake, improvement in peak oxygen uptake (pVO2) by cardiopulmonary exercise testing (CPET), improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), improvement in quality of life, improvement in quality of life as measured by PRO questionnaire, improvement in NYHA Functional Classification by one or more class(es), improvement in post-Valsalva left ventricular outflow tract gradient (LVOT-G), and improvement in total workload during CPET. 
     
     
         80 . (canceled) 
     
     
         81 . The method of  claim 79 , wherein the method results in one or more of:
 (a) change from baseline of ≥1.5 mL/kg/min in pVO2 and improvement in NYHA Functional Class by one or more class(es);   (b) change from baseline of ≥3.0 mL/kg/min in pVO2 and no worsening of NYHA Functional Class;   (c) improvement in KCCQ-OSS or KCCQ-CSS by at least 5 points, at least 10 points, or at least 20 points;   (d) LVOT-G<30 mmHg, post-Valsalva LVOT-G<50 mmHg, and improvement in NYHA Functional Class by one or more class(es).   
     
     
         82 - 87 . (canceled)