Granted Patent B1

US 12,370,179 · App. 18/909,401 · Granted Jul 29, 2025

Inventors: Fady Malik (Burlingame, CA); Stuart Kupfer (Highland Park, IL); Stephen B. Heitner (Portland, OR); Laura Ann Robertson (San Francisco, CA); Lixin Meng (Cupertino, CA); Anna Osmukhina (Portland, OR); Qi Wohltman (Belmont, CA)

Assignee: CYTOKINETICS, INC.

A61K31/4245A61P9/00

Abstract

Claims (38)

1. 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, wherein the first daily dose is about 5 mg and the first time period is about 2 weeks; 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, wherein the second time period is about 2 weeks, wherein the one or more components of the first echocardiogram comprises a LVEF and a post-Valsalva LVOT-G, and

wherein the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 10 mg when the LVEF of the first echocardiogram is at or above 55% and the post-Valsalva LVOT-G of the first echocardiogram is at or above 30 mmHg, or wherein the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, when either of the following conditions are met on the first echocardiogram: (1) the LVEF is at or above 50% and below 55%; or (2) the LVEF is at or above 55% and the post-Valsalva LVOT-G is below 30 mmHg.

2. The method of claim 1 , wherein the second daily dose of Compound 1, or the 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 the 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, wherein the third time period is about 2 weeks;

wherein the one or more components of the second echocardiogram comprises a LVEF and a post-Valsalva LVOT-G, and

wherein the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is greater than the second daily dose of Compound 1 when the LVEF of the second echocardiogram is at or above 55% and the post-Valsalva LVOT-G of the second echocardiogram is at or above 30 mmHg, wherein the third daily dose is about 10 mg or about 15 mg, or

wherein the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is lower than the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, or the administering of Compound 1, or the pharmaceutically acceptable salt thereof, to the patient is terminated, when the LVEF of the second echocardiogram is below 50%, or

wherein the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, when either of the following conditions are met on the second echocardiogram: (1) the LVEF is at or above 50% and below 55%; or (2) the LVEF is at or above 55% and the post-Valsalva LVOT-G is below 30 mmHg.

3. The method of claim 2 , wherein the administering of Compound 1, or the pharmaceutically acceptable salt thereof, to the patient is terminated when the LVEF of the second echocardiogram is below 50% and the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof is the same as the first daily dose of Compound 1.

4. The method of claim 2 , wherein the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, when the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is higher than the first daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, and the LVEF of the second echocardiogram is below 50%.

5. The method of claim 2 , wherein the first daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 5 mg of Compound 1, the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 5 mg or about 10 mg of Compound 1, and the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 5 mg, about 10 mg, or about 15 mg of Compound 1.

6. The method of claim 2 , wherein the third daily dose of Compound 1, or the 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 1, or the 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, wherein the one or more components of the third echocardiogram comprises a LVEF and a post-Valsalva LVOT-G, and:

wherein the fourth daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is greater than the third daily dose of Compound 1 when the LVEF of the third echocardiogram is at or above 55% and the post-Valsalva LVOT-G of the third echocardiogram is at or above 30 mmHg, wherein the fourth daily dose is about 10 mg or about 15 mg or about 20 mg, or

wherein the fourth daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is lower than the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, or the administering of Compound 1, or the pharmaceutically acceptable salt thereof, to the patient is terminated, when the LVEF of the third echocardiogram is below 50%, or

wherein the fourth daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, when either of the following conditions are met on the third echocardiogram: (1) the LVEF is at or above 50% and below 55%; or (2) the LVEF is at or above 55% and the post-Valsalva LVOT-G is below 30 mmHg.

7. The method of claim 6 , wherein the administering of Compound 1, or the pharmaceutically acceptable salt thereof, to the patient is terminated when the LVEF of the third echocardiogram is below 50% and the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or the pharmaceutically acceptable salt thereof.

8. The method of claim 6 , wherein:

the fourth daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, when the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is higher than the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, and the LVEF of the third echocardiogram is below 50%; or

the fourth daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the first daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, when the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is the same as the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, and the LVEF of the third echocardiogram is below 50%.

9. The method of claim 6 , wherein the first daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 5 mg of Compound 1, the second daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 10 mg of Compound 1, the third daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 15 mg of Compound 1, and the fourth daily dose of Compound 1, or the pharmaceutically acceptable salt thereof, is about 20 mg of Compound 1.

10. The method of claim 6 , wherein the fourth time period is about 2 weeks.

11. The method of claim 1 , wherein the patient is administered disopyramide or another antiarrhythmic medication during the treatment with Compound 1, or the pharmaceutically acceptable salt thereof.

12. The method of claim 1 , 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 the pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the patient is a CYP2D6 poor metabolizer.

14. The method of claim 1 , wherein the method does not include taking a blood sample of the patient.

15. The method of claim 1 , 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.

16. The method of claim 15 , wherein the method results in one or more of:

(a) change from baseline of ≥3.0 mL/kg/min in pVO2 and no worsening of NYHA Functional Class;

(b) improvement in KCCQ-OSS or KCCQ-CSS by at least 5 points, at least 10 points, or at least 20 points; or

(c) LVOT-G <30 mmHg, post-Valsalva LVOT-G <50 mmHg, and improvement in NYHA Functional Class by one or more class(es).

17. The method of claim 1 , wherein administration of Compound 1, or the pharmaceutically acceptable salt thereof, is stopped when the LVEF is below 50%.

18. The method of claim 15 , wherein the method results in change from baseline of >1.5 mL/kg/min in pVO2 and improvement in NYHA Functional Class by one or more class(es).

19. The method of claim 1 , wherein the LVEF of the first echocardiogram is a biplane LVEF.

20. The method of claim 2 , wherein the LVEF of the second echocardiogram is a biplane LVEF.

21. The method of claim 6 , wherein the LVEF of the third echocardiogram is a biplane LVEF.

Assignments (1)

Continuity (6)

References Cited (400)