Treatment methods using myosin modulators

Abstract

This invention provides a method for treating the pathophysiology of HCM and other diseases using myosin inhibitors. [Solution] This specification discloses a therapeutic method comprising administering a therapeutically effective amount of a myosin modulator or a pharmaceutically acceptable salt thereof to a subject in need, and a diagnostic method useful in connection with such therapies. Findings from clinical trials using mabacamten and from the use of mabacamten and other myosin inhibitors in preclinical settings provide novel insights into how myosin inhibitors can be beneficially used to influence the pathogenesis of HCM and other diseases.

Claims

1. A method for treating a disease of interest, comprising administering a therapeutically effective amount of myosin modulator to a subject in need thereof, wherein the subject has (a) elevated cardiac troponin levels and / or (b) elevated NT-proBNP or BNP.

2. The method according to claim 1, wherein the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT).

3. The method according to claim 2, wherein the subject further has normal systolic contractility or systolic hypercontractility, and the left ventricular ejection fraction of the subject is greater than 50%.

4. The method according to any one of claims 1 to 3, wherein the subject is suffering from symptoms of a cardiovascular disease.

5. The method according to any one of the prior claims, wherein the symptoms are selected from the group consisting of shortness of breath, dizziness, chest pain, syncope, or limitation of activities of daily living.

6. The method according to claim 5, wherein the restriction on activities of daily living is selected from the group consisting of restrictions on personal care, mobility, or eating.

7. The method according to any one of the prior claims, wherein the subject has one or a combination of myocardial diastolic dysfunction, elevated left ventricular filling pressure, left ventricular hypertrophy, and left atrial enlargement (LAE).

8. The method according to any one of the prior claims, wherein the object further has an increased E / e'.

9. The method according to any one of the prior claims, wherein the subject has a normal or hypersystolic left ventricular ejection fraction (LVEF).

10. The method according to claim 9, wherein the normal LVEF is between 52 and 74%.

11. The method according to any one of the prior claims, wherein the subject is suffering from diastolic dysfunction, left ventricular hypertrophy, malignant left ventricular hypertrophy, angina pectoris, ischemia, hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), or heart failure with preserved ejection fraction (HFpEF).

12. The method according to any one of the prior claims, wherein the subject is suffering from valvular aortic stenosis, a combination of LV systolic and diastolic dysfunction, idiopathic RV hypertrophy, chronic kidney disease, aortic regurgitation, Tetralogy of Fallot, mitral stenosis, Noonan syndrome, or acute coronary syndrome.

13. The method according to any one of the prior claims, wherein the subject has been diagnosed with HCM.

14. The method according to claim 13, wherein the HCM is an occlusive HCM.

15. The method according to claim 13, wherein the HCM is a non-obstructive HCM.

16. The method according to any one of the prior claims, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

17. The method according to any one of the prior claims, wherein the subject has experienced a reduction in the risk of a major cardiovascular event, and the major cardiovascular event is selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

18. The method according to any one of the prior claims, wherein the subject experiences a statistically significant reduction in the level(s) of cardiac troponin and / or NT-proBNP or BNP.

19. A method for treating the target disease, This includes administering a therapeutically effective dose of a myosin inhibitor to the subject in need thereof. The subject is suffering from a disease including oHCM, nHCM, HFpEF, diastolic dysfunction, left ventricular hypertrophy (LVH), malignant LVH, ischemia, or angina pectoris; or The patient suffers from a disease including valvular aortic stenosis, a combination of LV systolic and diastolic dysfunction, idiopathic RV hypertrophy, chronic kidney disease, aortic regurgitation, Tetralogy of Fallot, mitral stenosis, Noonan syndrome, or acute coronary syndrome, and the above method is A step of recommending that the subject be tested for elevated cardiac troponin levels and / or elevated NT-proBNP or BNP levels; If the subject has (a) elevated cardiac troponin levels and / or (b) elevated NT-proBNP or BNP levels, the step of administering a therapeutically effective dose of a myosin inhibitor to the subject, The method, including the method described above.

20. The method according to claim 19, wherein the cardiac troponin measured is cTnI or cTnT.

21. The method according to claim 19, further comprising the step of recommending that the subject be tested for elevated NT-proBNP or BNP levels, and then administering the myosin inhibitor if elevated cardiac troponin levels and elevated NT-proBNP or BNP levels are observed.

22. The method according to any one of claims 19 to 21, further comprising the step of recommending that the subject be evaluated for an elevated E / e', and then administering the myosin inhibitor if an elevated E / e' is observed.

23. The method according to any one of claims 19 to 22, wherein the disease of the subject is diagnosed according to the New York Heart Association (NYHA) classification.

24. The method according to claim 23, further comprising the step of evaluating the NYHA classification score of the subject before and after administration of the therapeutically effective amount of the myosin inhibitor, wherein a decrease in the NYHA score after administration of the myosin inhibitor indicates a reduction in the severity of the disease in the subject.

25. The method according to claim 23, further comprising the step of administering a myosin inhibitor until the subject moves from NYHA class III to class II, or from class II to class I.

26. The method according to any one of claims 19 to 25, wherein the NYHA classification score of the subject decreases from grade III to grade II, or from grade II to grade I, after administration of the therapeutically effective amount of the myosin inhibitor.

27. The method according to any one of claims 19 to 22, wherein the disease of the subject is diagnosed according to the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.

28. The method according to claim 27, further comprising the step of determining the KCCQ score of the subject before and after administration of the therapeutically effective amount of the myosin inhibitor, wherein an increase in the KCCQ score after administration of the myosin inhibitor indicates a reduction in the severity of the disease in the subject.

29. The maximum oxygen consumption (VO2) of the subject during exercise before and after administration of the therapeutically effective dose of the myosin inhibitor. ２ ) and / or VE / CO ２ Alternatively, VE / VCO ２ This further includes evaluating the slope, The method according to any one of claims 19 to 28, wherein the increase in maximum oxygen consumption in the subject after administration of the myosin inhibitor indicates a reduction in the degree of HCM or at least one symptomatic component or condition in the subject.

30. The method according to any one of claims 19 to 29, wherein the subject is diagnosed as eligible for surgical intervention or percutaneous ablation to treat the disease.

31. The method according to any one of claims 19 to 29, wherein the subject has an LVEF of more than 50%.

32. The method according to claim 30, wherein the disease is non-obstructive HCM.

33. The method according to any one of claims 19 to 32, wherein the myosin modulator is a myosin inhibitor.

34. The method according to claim 33, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

35. The method according to any one of the prior claims, wherein the subject has experienced a reduction in the risk of a major cardiovascular event, and the major cardiovascular event is selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

36. The method according to any one of the prior claims, wherein the subject experiences a statistically significant reduction in the level of (a) cardiac troponin and / or (b) NT-proBNP or BNP.

37. A method for reducing the mortality rate of a subject suffering from symptoms resulting from cardiovascular disease, comprising: administering a therapeutically effective initiating dose of a myosin modulator to the subject to achieve a stable, desired clinical state; and subsequently administering a myosin inhibitor reduction regimen to maintain or improve the desired clinical state.

38. The method according to claim 37, wherein the symptoms resulting from the cardiovascular disease are shortness of breath, dizziness, chest pain, syncope, fatigue, or limitation of daily living activities.

39. The method according to claim 38, wherein the limitations on daily living activities are selected from the group consisting of restrictions on personal care, mobility, or eating.

40. The method according to claim 37, wherein the cardiovascular disease is selected from the group consisting of oHCM, nHCM, HFpEF, LVH, malignant LVH, ischemia, or angina pectoris.

41. The method according to any one of claims 37 to 40, wherein the myosin modulator is a myosin inhibitor.

42. The method according to claim 41, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

43. The method according to claim 42, wherein the reduced daily medication regimen is about one-third, one-fourth, or one-fifth of the amount of mavacamten required to maintain the plasma level of the subject mavacamten.

44. The method according to claim 43, wherein the plasma level of mabacamten is 200 to 750 ng / mL.

45. The method according to any one of claims 37 to 44, wherein the dose reduction regimen is less than 5 mg per day, 4 mg or less per day, 3 mg or less per day, 2 mg or less per day, or 1 mg or less per day.

46. The method according to claim 42, wherein the therapeutically effective dose of mabacamten is about 5 mg to about 15 mg, and the dose reduction regimen is less than 5 mg of mabacamten per day.

47. The method according to any one of claims 37 to 46, wherein the dose reduction regimen is administered to the subject over a long period of time.

48. The method according to any one of the prior claims, wherein the patient is suffering from a disease selected from the group consisting of oHCM, nHCM, HFpEF, LVH, or ischemia.

49. The method according to any one of the prior claims, wherein the subject experiences a reduction in the risk of major cardiovascular events.

50. The method according to any one of the prior claims, wherein the major cardiovascular event is selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

51. A method for treating a subject after septal reduction therapy (SRT), comprising administering a myosin modulator reduction regimen to the subject to maintain a stable and desired clinical state after septal reduction therapy.

52. The method according to claim 51, wherein the myosin modulator is a myosin inhibitor.

53. The method according to claim 51, wherein the myosin inhibitor is mabacamtene or a pharmaceutically acceptable salt thereof.

54. The method according to claim 53, wherein the dose reduction regimen is a daily dose of mabacamten to achieve a plasma concentration of 50 to 350 ng / ml, or less than 5 mg per day, 4 mg or less per day, 3 mg or less per day, 2.5 mg or less per day, or 1 mg or less per day.

55. A method for preventing HCM or LVH in a subject at risk of developing HCM or LVH, comprising the step of administering a myosin modulator to the subject at risk and in need thereof, wherein the subject has (a) elevated cardiac troponin levels and / or (b) elevated NT-proBNP or BNP levels.

56. The method according to claim 55, wherein the subject at risk further has an elevated NT-proBNP or BNP level.

57. The method according to claim 55 or 56, wherein the myosin modulator is a myosin inhibitor.

58. The method according to claim 57, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

59. The method according to any one of claims 55 to 58, wherein the HCM is oHCM or nHCM.

60. The method according to any one of claims 55 to 58, wherein the subject has Noonan syndrome.

61. The method according to any one of claims 55 to 60, wherein the subject is a child, an adolescent, or an adult.

62. A method for preventing HCM or LVH in a subject at risk of developing HCM or LVH, comprising the step of administering a low dose of a myosin modulator to the subject in need to completely or partially prevent the development of HCM or LVH.

63. The method according to claim 62, wherein the myosin modulator is a myosin inhibitor.

64. The method according to claim 63, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof administered over a long period of time.

65. The method according to claims 62 to 64, wherein the subject being treated is a child, adolescent, or adult.

66. The method according to any one of claims 55 to 65, wherein the subject has symptoms of HCM or LVH, including shortness of breath, dizziness, chest pain, syncope, fatigue, and limitations in daily living activities.

67. The method according to claim 66, wherein the restriction on activities of daily living is selected from the group consisting of restrictions on personal care, mobility, or eating.

68. The method according to any one of claims 62 to 67, wherein the low dose of the myosin inhibitor is one-third to one-fifth of the amount of such myosin inhibitor required to reduce the LVOT gradient in a patient with oHCM.

69. The method according to any one of claims 62 to 68, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

70. The method according to claim 69, wherein the low dose of mabacamten is less than 5 mg per day, or an amount sufficient to maintain a plasma concentration of mabacamten between 50 and 350 ng / mL.

71. The method according to claim 69, wherein the low dose of mabacamten is 1 mg, 2 mg, 2.5 mg, or 3 mg per day.

72. The method according to any one of claims 62 to 71, wherein the drug regimen of myosin inhibitors is administered to the subject in the early stages of HCM or LVH development.

73. The method according to claim 72, wherein the HCM is oHCM or nHCM.

74. A method for reducing adverse events in a subject associated with reduced cardiac output after treatment with a myosin inhibitor, comprising the step of administering a therapeutic dose of a beta-adrenergic agonist to the subject.

75. The method according to claim 74, wherein the beta-adrenergic agonist is dobutamine.

76. The method according to claim 74, wherein the beta-adrenergic agonist is levocimendan.

77. The method according to claim 75, wherein the therapeutic dose of the beta-adrenergic agonist is a dobutamine infusion of about 5 μg / kg / min to about 10 μg / kg / min.

78. The method according to claim 76, wherein the therapeutic dose of the beta-adrenergic agonist is an infusion of about 0.2 to about 0.4 μmol / kg of levocimendan over a period of about 30 minutes.

79. The method according to any one of claims 74 to 78, further comprising the additional step of administering intravenous volume replacement and / or an arterial vasoconstrictor to the subject.

80. The method according to claim 79, wherein the arterial vasoconstrictor is an adrenergic agonist.

81. The method according to any one of claims 74 to 80, wherein the myosin inhibitor is mabacamten.

82. The method according to claim 74, further comprising monitoring the plasma concentration of mabacamten in the subject and determining, based on the measured plasma concentration, that the subject has been administered an amount exceeding the therapeutic dose of mabacamten.

83. The method according to claim 82, wherein the amount exceeding the therapeutic dose of mabacamten is the dose of mabacamten that produces a plasma concentration of mabacamten exceeding approximately 1000 ng / mL in the subject.

84. The method according to any one of claims 1 to 83, wherein the myosin inhibitor is mabacamten.

85. The method according to claim 84, wherein the mabacamten is a type A crystal of mabacamten.

86. A method for treating a target disease, comprising administering a therapeutically effective amount of a myosin modulator to a subject in need thereof, wherein the subject has elevated cardiac troponin levels and / or an elevated E / e'.

87. The method according to claim 86, wherein the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT).

88. The method according to claim 87, wherein the cardiac troponin is cTnI or high-sensitivity cTnI (hs-cTnI).

89. The method according to any one of claims 86 to 88, wherein the subject is suffering from symptoms of a cardiovascular disease.

90. The method according to claim 89, wherein the symptoms are selected from the group consisting of shortness of breath, dizziness, chest pain, fainting, or limitation of daily living activities.

91. The method according to claim 90, wherein the restrictions on daily living activities are selected from the group consisting of restrictions on personal care, mobility, or eating.

92. The method according to any one of claims 86 to 91, wherein the subject further has an elevated NT-proBNP or BNP level.

93. The method according to any one of claims 86 to 92, wherein the target has an increased E / e'.

94. The method according to any one of claims 86 to 93, wherein the subject has a normal or hypersystolic left ventricular ejection fraction (LVEF).

95. The method according to claim 94, wherein the normal LVEF is between 52 and 74%.

96. The method according to any one of claims 86 to 95, wherein the subject is suffering from diastolic dysfunction, left ventricular hypertrophy (LVH), malignant LVH, angina pectoris, ischemia, hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), or heart failure with preserved ejection fraction (HFpEF).

97. The method according to claim 96, wherein the subject has been diagnosed with HFpEF.

98. The method according to claim 97, wherein the subject has been diagnosed with HCM.

99. The method according to claim 98, wherein the HCM is an occlusive HCM.

100. The method according to claim 98, wherein the HCM is a non-obstructive HCM.

101. The method according to claims 86 to 100, wherein the myosin modulator is a myosin inhibitor.

102. The method according to claim 101, wherein the myosin inhibitor is mabacamtene or a pharmaceutically acceptable salt thereof.

103. The method according to claims 86 to 102, wherein the subject has experienced a reduction in the risk of major cardiovascular events, and the major cardiovascular events are selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

104. The method according to any one of claims 86 to 103, wherein the subject experiences a statistically significant reduction in the level(s) of cardiac troponin and / or NT-proBNP or BNP.

105. A method for treating a target disease, comprising administering a therapeutically effective amount of a myosin inhibitor to the subject in need thereof, The subject suffers from a disease including oHCM, nHCM, HFpEF, diastolic dysfunction, left ventricular hypertrophy (LVH), malignant LVH, ischemia, or angina pectoris, and the method is A step recommending that the subject be tested for elevated cardiac troponin levels and / or elevated E / e'; The step of administering a therapeutically effective dose of a myosin inhibitor to the subject if the subject has elevated cardiac troponin levels and / or elevated E / e', The method, including the method described above.

106. The method according to claim 105, wherein the cardiac troponin measured is cTnI or cTnT.

107. The method according to claim 105, further comprising the step of recommending that the subject be tested for elevated E / e', and then administering the myosin inhibitor if elevated cardiac troponin levels and elevated E / e' are observed.

108. The method according to any one of claims 105 to 107, further comprising the steps of recommending that the subject be evaluated for elevated NT-proBNP or BNP, and then administering the myosin inhibitor if elevated cardiac troponin levels, elevated NT-proBNP or BNP levels, and elevated E / e' are observed.

109. The method according to any one of claims 105 to 108, wherein the disease of the subject is diagnosed according to the New York Heart Association (NYHA) classification.

110. The method according to claim 109, further comprising the step of evaluating the NYHA classification score of the subject before and after administration of the therapeutically effective amount of the myosin inhibitor, wherein a decrease in the NYHA score after administration of the myosin inhibitor indicates a reduction in the severity of the disease in the subject.

111. The method according to claim 109, further comprising the step of administering a myosin inhibitor until the subject moves from NYHA Class III to Class II, or from Class II to Class I.

112. The method according to any one of claims 105 to 111, wherein the NYHA classification score of the subject decreases from grade III to grade II, or from grade II to grade I, after administration of the therapeutically effective amount of the myosin inhibitor.

113. The method according to any one of claims 105 to 108, wherein the disease of the subject is diagnosed according to the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.

114. The method according to claim 113, further comprising the step of determining the KCCQ score of the subject before and after administration of the therapeutically effective amount of the myosin inhibitor, wherein an increase in the KCCQ score after administration of the myosin inhibitor indicates a reduction in the severity of the disease in the subject.

115. The maximum oxygen consumption (VO2) and / or VE / VCO2 in the subject during exercise before and after administration of the therapeutically effective dose of the myosin inhibitor. ２ The method according to any one of claims 105 to 114, further comprising evaluating the slope, wherein the maximum oxygen consumption (VO2) of the subject is increasing.

116. The method according to any one of claims 105 to 115, wherein the disease is HFpEF.

117. The method according to any one of claims 105 to 115, wherein the disease is obstructive HCM.

118. The method according to any one of claims 105 to 115, wherein the disease is non-obstructive HCM.

119. The method according to any one of claims 105 to 118, wherein the myosin inhibitor is mabacamtene or a pharmaceutically acceptable salt thereof.

120. The method according to any one of claims 105 to 119, wherein the subject has experienced a reduction in the risk of major cardiovascular events, and for example, the major cardiovascular events are selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

121. The method according to any one of claims 105 to 120, wherein the subject experiences a statistically significant reduction in the level(a) cardiac troponin and / or (b) NT-proBNP or BNP.

122. After administration of the therapeutically effective dose of the myosin inhibitor, the subject obtained pVO2 ２ Improvements to the NYHA classification, and optional improvements to the NYHA classification, for example, (i) pVO ２ Improvement of at least 1.5 mL / kg / min and reduction of NYHA classification of grade 1 or higher, (ii) pVO without deterioration of NYHA classification ２ The method according to any one of claims 105 to 121, which achieves an improvement of at least 3.0 mL / kg / min.

123. A method of administering mabacamten or a pharmaceutically acceptable salt thereof to a subject suffering from HFpEF, Administer a first dose of mabacamten or a pharmaceutically acceptable salt thereof to the subject having elevated NT-proBNP levels and / or elevated cTnT and / or elevated cTnI; Measuring the second NT-proBNP or BNP level of the subject; If the second NT-proBNP or BNP level is not at least 15-75% lower than the first NT-proBNP or BNP level, administer a second dose of mabacamten or a pharmaceutically acceptable salt thereof exceeding the first dose during the second treatment period; and If the second NT-proBNP or BNP level is at least 15-75% lower than the first NT-proBNP or BNP level, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period. The method, including the method described above.

124. If the second NT-proBNP or BNP level is not at least 40-60% lower than the first NT-proBNP or BNP level, administer the second dose of mabacamten or a pharmaceutically acceptable salt thereof in excess of the first dose during the second treatment period; and If the second NT-proBNP or BNP level is at least 40-60% lower than the first NT-proBNP or BNP level, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period. The method according to claim 122, including the method described in claim 122.

125. If the second NT-proBNP or BNP level is not at least 50% lower than the first NT-proBNP or BNP level, administer the second dose of mabacamten or a pharmaceutically acceptable salt thereof in excess of the first dose during the second treatment period; and If the second NT-proBNP or BNP level is at least 50% lower than the first NT-proBNP or BNP level, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period. The method according to claim 123, including the method described in claim 123.

126. The method according to any one of claims 122 to 124, wherein the subject has NT-proBNP or high BNP values.

127. The method according to claim 125, wherein the first NT-proBNP or BNP level is an elevated level.

128. The method according to any one of claims 122 to 126, further comprising measuring a first LVEF of the subject, and measuring a second LVEF of the subject after the first LVEF and after the start of a first treatment period.

129. The method according to claim 127, further comprising measuring the second LVEF at the end of the first treatment period, after its completion, or within four weeks prior to its completion.

130. If the second NT-proBNP or BNP level is not at least 15-75% lower than the first NT-proBNP or BNP level, and the second LVEF is not at least 10-20% lower than the first LVEF, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 127 or 128, wherein if the second NT-proBNP or BNP level is at least 15 to 75% lower than the first NT-proBNP or BNP level, or if the second LVEF is at least 10 to 20% lower than the second LVEF, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

131. If the second NT-proBNP or BNP level is not at least 40-60% lower than the first NT-proBNP or BNP level, and the second LVEF is not at least 10-20% lower than the first LVEF, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 129, wherein if the second NT-proBNP or BNP level is at least 40-60% lower than the first NT-proBNP or BNP level, or if the second LVEF is at least 10-20% lower than the second LVEF, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

132. If the second NT-proBNP or BNP level is not at least 50% lower than the first NT-proBNP or BNP level, and the second LVEF is not at least 15% lower than the first LVEF, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 130, wherein if the second NT-proBNP or BNP level is at least 50% lower than the first NT-proBNP or BNP level, or if the second LVEF is at least 15% lower than the second LVEF, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

133. The method according to any one of claims 122 to 130, wherein the first NT-proBNP or BNP level is measured before the first treatment period.

134. The method according to claim 132, wherein the first NT-proBNP or BNP level is measured immediately before or within two weeks before the first treatment period.

135. The method according to any one of claims 122 to 130, wherein the second NT-proBNP or BNP level is measured during the first treatment period.

136. The method according to claim 133, wherein the second NT-proBNP or BNP level is measured at the end of the first treatment period or within four weeks thereafter.

137. A method of administering mabacamten or a pharmaceutically acceptable salt thereof to a subject suffering from HFpEF, To measure the first cardiac troponin level of the subject; During the first treatment period, administer a first dose of mabacamten or a pharmaceutically acceptable salt thereof to the subject; To measure the second cardiac troponin level of the subject; If the second cardiac troponin level is not at least 10-50% lower than the first cardiac troponin level, administer a second dose of mabacamten or a pharmaceutically acceptable salt thereof exceeding the first dose during the second treatment period; and If the second cardiac troponin level is at least 10-50% lower than the first cardiac troponin level, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period. The method, including the method described above.

138. If the second cardiac troponin level is not at least 20-40% lower than the first cardiac troponin level, administer the second dose of mabacamten or a pharmaceutically acceptable salt thereof in excess of the first dose during the second treatment period; and The method according to claim 136, further comprising administering the first dose of mabacamten or a pharmaceutically acceptable salt thereof during the second treatment period if the second cardiac troponin level is at least 20 to 40 percent lower than the first cardiac troponin level.

139. If the second cardiac troponin level is not at least 30% lower than the first cardiac troponin level, administer the second dose of mabacamten or a pharmaceutically acceptable salt thereof in excess of the first dose during the second treatment period; and The method according to claim 137, further comprising administering the first dose of mabacamten or a pharmaceutically acceptable salt thereof during the second treatment period if the second cardiac troponin level is at least 30% lower than the first cardiac troponin level.

140. The method according to any one of claims 136 to 138, wherein the subject has NT-proBNP or high BNP values.

141. The method according to any one of claims 136 to 139, wherein the subject has elevated cardiac troponin levels.

142. The method according to any one of claims 136 to 140, wherein the cardiac troponin measured is cTnI or cTnT.

143. The method according to claim 141, wherein the cardiac troponin level to be measured is hs-cTnI.

144. The method according to any one of claims 136 to 142, further comprising measuring a first LVEF of the subject, and measuring a second LVEF of the subject after the first LVEF and after the start of the first treatment period.

145. The method according to claim 143, further comprising measuring the second LVEF at the end of the first treatment period, after its completion, or within two weeks prior to its completion.

146. If the second cardiac troponin level is not at least 10-50% lower than the first cardiac troponin level, and the second LVEF is not at least 10-20% lower than the first LVEF, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 143 or 144, wherein if the second cardiac troponin level is at least 10 to 50% lower than the first cardiac troponin level, or the second LVEF is at least 10 to 20% lower than the second LVEF, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

147. If the second cardiac troponin level is not at least 20-40% lower than the first cardiac troponin level, and the second LVEF is not at least 10-20% lower than the first LVEF, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 145, wherein if the second cardiac troponin level is at least 20-40% lower than the first cardiac troponin level, or the second LVEF is at least 10-20% lower than the second LVEF, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

148. If the second cardiac troponin level is not at least 30% lower than the first cardiac troponin level, and the second LVEF is not at least 15% lower than the first LVEF, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 146, wherein if the second cardiac troponin level is at least 30% lower than the first cardiac troponin level, or the second LVEF is at least 15% lower than the second LVEF, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

149. The method according to any one of claims 136 to 147, further comprising measuring a first NT-proBNP or BNP level of the subject, and measuring a second NT-proBNP or BNP level of the subject after the first NT-proBNP or BNP level and after the commencement of the first treatment period.

150. The method according to claim 148, further comprising measuring the second NT-proBNP or BNP level at the end of the first treatment period, after its completion, or within four weeks prior to its completion.

151. If the second cardiac troponin level is not at least 10-50% lower than the first cardiac troponin level, and the second NT-proBNP or BNP level is not more than 20-60% higher than the first NT-proBNP or BNP level, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 148 or 149, wherein if the second cardiac troponin level is at least 10 to 50% lower than the first cardiac troponin level, or the second NT-proBNP or BNP level is more than 20 to 60% higher than the first NT-proBNP or BNP level, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

152. If the second cardiac troponin level is not at least 20-40% lower than the first cardiac troponin level, and the second NT-proBNP or BNP level is not more than 40-55% higher than the first NT-proBNP or BNP level, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 150, wherein if the second cardiac troponin level is at least 20-40% lower than the first cardiac troponin level, or if the second NT-proBNP or BNP level is more than 40-55% higher than the first NT-proBNP or BNP level, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

153. If the second cardiac troponin level is not at least 30% lower than the first cardiac troponin level, and the second NT-proBNP or BNP level is not more than 50% higher than the first NT-proBNP or BNP level, then during the second treatment period, the second dose of mabacamten or a pharmaceutically acceptable salt thereof is administered in excess of the first dose; The method according to claim 156, wherein if the second cardiac troponin level is at least 30% lower than the first cardiac troponin level, or the second NT-proBNP or BNP level is more than 50% higher than the first NT-proBNP or BNP level, the first dose of mabacamten or a pharmaceutically acceptable salt thereof is administered during the second treatment period.

154. The method according to any one of claims 136 to 152, wherein the first cardiac troponin level is measured before the first treatment period.

155. The method according to claim 153, wherein the first cardiac troponin level is measured immediately before or within two weeks before the first treatment period.

156. The method according to any one of claims 136 to 154, wherein the second cardiac troponin level is measured during the first treatment period.

157. The method according to claim 155, wherein the second cardiac troponin level is measured at the end of the first treatment period or within four weeks thereafter.

158. The method according to any one of claims 122 to 156, wherein the first dose is approximately 1 mg to approximately 5 mg.

159. The method according to claim 157, wherein the first dose is approximately 2.5 mg.

160. The method according to any one of claims 122 to 158, wherein the second dose is approximately 2.5 mg to approximately 10 mg.

161. The method according to claim 159, wherein the second dose is approximately 5 mg.

162. The method according to any one of claims 122 to 160, wherein the second dose is approximately 1.5 to approximately 3 times the first dose.

163. The method according to claim 161, wherein the second dose is approximately twice the first dose.

164. The method according to any one of claims 122 to 162, wherein the first dose is administered daily during the first treatment period.

165. The method according to any one of claims 122 to 163, wherein the first treatment period is at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, at least twelve weeks, four to twenty weeks, ten to sixteen weeks, or about fourteen weeks.

166. The method according to any one of claims 122 to 164, wherein the second dose is administered daily during the second treatment period.

167. The method according to any one of claims 122 to 165, wherein the second treatment period is at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, or at least twelve weeks.

168. The aforementioned subjects are as follows: Previous hospitalization for heart failure accompanied by X-ray evidence of pulmonary congestion; Elevated left ventricular end-diastolic pressure or pulmonary capillary wedge pressure at rest or during exercise; NT-ProBNP or high BNP values; and Echocardiographic evidence of a medial E / e' ratio ≥ 15 or left atrial enlargement accompanied by long-term treatment with loop diuretics, The method according to any one of claims 122 to 166, wherein the method has prior objective evidence of heart failure as indicated by one or more of the following.

169. The method according to any one of claims 122 to 167, wherein the target has an increased E / e'.

170. A method for treating a target disease, comprising administering a therapeutically effective amount of a myosin inhibitor to a subject in need thereof, wherein the subject has elevated cardiac troponin levels and / or elevated NT-proBNP or BNP and / or elevated E / e'.

171. The method according to claim 169, wherein the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT).

172. The method according to claim 170, wherein the cardiac troponin is cTnI or high-sensitivity cTnI (hs-cTnI).

173. The method according to claim 169, wherein the elevated troponin level exceeds the upper limit of normal (ULN).

174. The method according to claim 172, wherein the ULN of the cTnT is about 0.014 ng / mL.

175. The method according to claim 172, wherein the ULN of the cTnI is approximately 47 pg / mL.

176. The method according to claim 169, wherein E / e' is greater than 10.

177. The method according to claim 169, wherein the aforementioned E / e' is the average E / e'.

178. The method according to claim 169, wherein E / e' is greater than 13.

179. The method according to claim 169, wherein the BNP is greater than 35 pg / mL.

180. The method according to claim 169, wherein the NT-proBNP is greater than 125 pg / mL.

181. The method according to claim 169, wherein the NT-proBNP is greater than 250 pg / mL.

182. The method according to claim 169, wherein the NT-proBNP is greater than 300 pg / mL.

183. The method according to claim 169, wherein the NT-proBNP is greater than 450 pg / mL.

184. The method according to claim 179, wherein the subject is 74 years of age or younger.

185. The method according to claim 182, wherein the subject is 75 years of age or older.

186. The method according to any one of claims 169 to 184, wherein the subject is suffering from symptoms of a cardiovascular disease.

187. The method according to claim 185, wherein the symptoms are selected from the group consisting of shortness of breath, dizziness, chest pain, fainting, or limitation of daily living activities.

188. The method according to claim 185, wherein the limitations on daily living activities are selected from the group consisting of restrictions on personal care, mobility, or eating.

189. The method according to any one of claims 169 to 187, wherein the subject suffers from diastolic dysfunction, elevated filling pressure, elevated left ventricular filling pressure, left atrial enlargement, maintenance of systolic function, or systolic hypercontractility.

190. The method according to any one of claims 169 to 187, wherein the subject is suffering from hypertrophic cardiomyopathy (HCM).

191. The method according to any one of claims 169 to 187, wherein the subject is suffering from left ventricular hypertrophy (LVH), malignant LVH, angina pectoris, ischemia, hypertrophic cardiomyopathy (HCM), or restrictive cardiomyopathy (RCM).

192. The method according to any one of claims 169 to 187, wherein the subject is suffering from heart failure with preserved ejection fraction (HFpEF).

193. The method according to claim 191, wherein the subject is suffering from shortness of breath, fatigue, palpitations (atrial fibrillation), chest discomfort, or edema.

194. The method according to claim 191, wherein the subject suffers from myocardial diastolic dysfunction, elevated LV filling pressure, left ventricular wall hypertrophy, left atrial enlargement, normal or hypercontractility, myocardial injury and fibrosis, or abnormal myocardial energy characteristics.

195. The method according to claim 191, wherein the subject suffers from reduced exercise tolerance, fatigue, malaise, increased recovery time after exercise, or ankle swelling.

196. The method according to any one of claims 169 to 187, wherein the subject has a normal or hypersystolic left ventricular ejection fraction (LVEF).

197. The method according to claim 195, wherein the normal LVEF is between 52 and 74%.

198. The method according to any one of claims 169 to 187, wherein the subject has been diagnosed with HCM.

199. The method according to claim 197, wherein the HCM is an occlusive HCM.

200. The method according to claim 197, wherein the HCM is a non-obstructive HCM.

201. The method according to any one of claims 169 to 199, wherein the myosin inhibitor is mabacamtene or a pharmaceutically acceptable salt thereof.

202. The method according to any one of claims 169 to 197, wherein the subject has experienced a reduction in the risk of major cardiovascular events, and for example, the major cardiovascular events are selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

203. The method according to any one of claims 169 to 201, wherein the subject experiences a statistically significant reduction in (a) cardiac troponin and / or (b) NT-proBNP or BNP and / or (c) the level(s) of E / e'.

204. A method for treating a target disease, comprising administering a therapeutically effective amount of a myosin inhibitor to a subject in need thereof, wherein the subject has a LVEF greater than 52%, and one or more of the following: (a) elevated cardiac troponin, (b) elevated NT-proBNP or BNP, and (c) elevated E / e'.

205. The method according to claim 203, wherein the subject maintains contractile function or has normal contractility or systolic hypercontractility.

206. The method according to claim 203, wherein the subject experiences a reduction in longitudinal global strain by treating the disease with the myosin inhibitor.

207. The method according to claim 203, wherein the subject has a functional impairment.

208. The method according to claim 203, wherein the subject experiences a reduction in left ventricular filling pressure by treating the disease with the myosin inhibitor.

209. The method according to claim 207, wherein the reduction is characterized by an improvement in the mean E / e'.

210. The method according to claim 203, wherein the subject has left ventricular hypertrophy or left atrial enlargement.

211. The method according to claim 209, wherein the subject has mild left ventricular hypertrophy.

212. The method according to claim 209 or 210, wherein by treating the disease with the myosin inhibitor, the subject experiences a reduction in left ventricular myocardial mass, left ventricular wall thickness, ventricular septal thickness, or left ventricular septal thickness.

213. The method according to any one of claims 203 to 211, wherein the myosin inhibitor is mabacamtene or a pharmaceutically acceptable salt thereof.

214. The method according to claim 212, wherein the therapeutically effective dose is approximately 2.5 mg to approximately 15 mg.

215. The method according to claim 213, wherein the therapeutically effective dose is approximately 2.5 mg to approximately 5 mg per day.

216. The method according to claim 213, wherein the therapeutically effective dose is approximately 5 mg to approximately 7.5 mg per day.

217. The method according to claim 213, wherein the therapeutically effective dose is approximately 7.5 mg to approximately 15 mg per day.

218. The method according to any one of claims 203 to 216, wherein the cardiac troponin is cardiac troponin T (cTnT).

219. The method according to claim 217, wherein the cardiac troponin is cardiac cTnI or high-sensitivity cTnI (hs-cTnI).

220. The method according to any one of claims 203 to 216, wherein the increased E / e' is greater than 10 or 13.

221. The method according to any one of claims 203 to 216, wherein the E / e' is the average E / e'.

222. The method according to any one of claims 203 to 216, wherein the BNP is greater than 35 pg / mL.

223. The method according to any one of claims 203 to 216, wherein the NT-proBNP is greater than 125 pg / mL.

224. The method according to claim 222, wherein the NT-proBNP is greater than 300 pg / mL.

225. The method according to any one of claims 203 to 223, wherein the subject is suffering from symptoms of a cardiovascular disease.

226. The method according to claim 224, wherein the symptoms include shortness of breath, dizziness, chest pain, fainting, or limitation of daily living activities.

227. The method according to claim 225, wherein the limitations on daily living activities are selected from the group consisting of restrictions on personal care, mobility, or eating.

228. The method according to any one of claims 203 to 226, wherein the subject experiences a reduction in the risk of a major cardiovascular event selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

229. The method according to any one of claims 203 to 224, wherein the treatment further comprises measuring the levels of (a) cardiac troponin and / or (b) NT-proBNP or BNP and / or (c) E / e' of the subject.

230. The method according to claim 228, wherein the cardiac troponin is cardiac troponin T (cTnT), high-sensitivity cTnT (hs-cTnT), cardiac troponin I (cTnI), or high-sensitivity cTnI (hs-cTnI).

231. The method according to any one of the prior claims, wherein the measurement is performed by echocardiography (ECHO), magnetic resonance imaging (MRI), computed tomography (CT) scan, or cardiac catheterization.

232. The method according to any one of claims 203 to 230, further comprising evaluating the NYHA classification score of the subject before and after administration of the therapeutically effective amount of mabacamtene or a pharmaceutically acceptable salt thereof, wherein a decrease in the NYHA score after administration of mabacamtene or a pharmaceutically acceptable salt thereof indicates a reduction in the severity of the disease of the subject.

233. The method according to claim 231, further comprising the step of administering a therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt until the subject moves from NYHA class III to class II, or from class II to class I.

234. The method according to any one of claims 203 to 232, further comprising determining the KCCQ score of the subject before and after administration of the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof, wherein an increase in the KCCQ score after administration of the myosin inhibitor indicates a reduction in the severity of the disease in the subject.

235. where the treatment further comprises evaluating the maximum oxygen consumption (VO ２ ), and / or the VE / VCO ２ slope during exercise in the subject before and after administration of the therapeutically effective amount of mavacamten or a pharmaceutically acceptable salt thereof, and wherein the maximum oxygen consumption (VO ２ ) of the subject is increased, the method according to any one of claims 203 to 233.

236. The method according to any one of claims 203 to 234, wherein the subject has experienced a reduction in the risk of major cardiovascular events, and the major cardiovascular events are selected from the group consisting of death, hospitalization due to exacerbation of the disease, and myocardial infarction.

237. The method according to claim 235, wherein the subject experiences a statistically significant reduction in the level(a) cardiac troponin and / or(b) NT-proBNP or BNP.

238. A method for treating a target disease, comprising administering a therapeutically effective amount of a myosin inhibitor to a subject in need thereof, wherein the subject has a LVEF of more than 50%, and one or more of (a) elevated cardiac troponin levels or (b) elevated NT-proBNP or BNP levels.

239. The method according to claim 237, wherein the subject maintains contractile function or has normal contractility or systolic hypercontractility.

240. The method according to claim 238, wherein the subject has an LVEF of 55% or more.

241. The method according to claim 238, wherein the object has a global strain (GLS) in the longitudinal direction of -15 or less.

242. The method according to claim 238, wherein the object has an s' of about 8.1 to about 9.

5.

243. The method according to claim 238, wherein the subject has a left chamber diameter shortening ratio (LVFS) of 25 or more.

244. The method according to claim 237, wherein the subject has an LVOT of more than 40 mmHg.

245. The method according to claim 237, wherein the subject has a functional impairment.

246. The method according to claim 244, wherein the subject has an E / A below the normal lower limit, and / or a septum e', lateral wall e', or mean e' below the normal lower limit.

247. The method according to claim 237, wherein the subject has an increase in LV filling pressure.

248. The method according to claim 246, wherein the subject has NT-proBNP exceeding 125 pg / ml or BNP exceeding 100 pg / ml.

249. The method according to claim 246, wherein the target has an E / e' of more than 10.

250. The method according to claim 246, wherein the subject experiences a reduction in left ventricular filling pressure by treating the disease with the myosin inhibitor.

251. The method according to claim 249, wherein the reduction is characterized by an improvement in the mean E / e'.

252. The method according to claim 237, wherein the subject has left ventricular hypertrophy.

253. The method according to claim 251, wherein the subject has left ventricular wall hypertrophy.

254. The method according to claim 251 or 252, wherein the subject has a left ventricular end-diastolic volume (LVEDV) below the lower limit of normal or less than approximately 40 to 45.

255. The method according to claim 251 or 252, wherein the subject has an IVS and / or LV rear WT of more than 10 mm, a maximum wall thickness of more than 1.2 mm, or an LVMI, LVM, or septal thickness outside the normal range.

256. The method according to any one of claims 251 to 254, wherein by treating the disease with the myosin inhibitor, the subject experiences a reduction in left ventricular myocardial mass, left ventricular wall thickness, ventricular septal thickness, or left ventricular septal thickness.

257. The method according to claim 237, wherein the subject has left atrial enlargement.

258. The method according to claim 256, wherein the subject has a left atrial volume exceeding the upper limit of normal.

259. The method according to claim 237, wherein the subject has myocardial injury and / or fibrosis.

260. The method according to claim 258, wherein the subject has elevated cardiac troponin levels.

261. The method according to claim 258, wherein the subject exhibits delayed gadolinium enhancement consistent with myocardial injury and / or fibrosis.

262. The method according to claim 258, wherein the subject exhibits a T1 mapping consistent with myocardial injury and / or fibrosis.

263. The method according to any one of claims 237 to 261, wherein the myosin inhibitor is mabacamtene or a pharmaceutically acceptable salt thereof.

264. The method according to claim 262, wherein the therapeutically effective dose is approximately 2.5 mg to approximately 15 mg.

265. The method according to claim 262, wherein the therapeutically effective dose is approximately 2.5 mg to approximately 5 mg per day.

266. The method according to claim 262, wherein the therapeutically effective dose is approximately 5 mg to approximately 7.5 mg per day.

267. The method according to claim 262, wherein the therapeutically effective dose is approximately 7.5 mg to approximately 15 mg per day.

268. The method according to any one of claims 237 to 266, wherein the cardiac troponin is cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT).

269. The method according to claim 267, wherein the cardiac troponin is cardiac troponin I (cTnI) or high-sensitivity cTnI (hs-cTnI).

270. The method according to any one of claims 237 to 268, wherein the BNP is greater than 100 pg / mL.

271. The method according to any one of claims 237 to 268, wherein the NT-proBNP is greater than 125 pg / mL.

272. The method according to claim 270, wherein the NT-proBNP is greater than 300 pg / mL.

273. The method according to any one of claims 237 to 271, wherein the subject is suffering from symptoms of a cardiovascular disease.

274. The method according to claim 272, wherein the symptoms include shortness of breath, dizziness, chest pain, fainting, or limitation of daily living activities.

275. The method according to claim 273, wherein the restriction on daily living activities is selected from the group consisting of restrictions on personal care, mobility, or eating.

276. The method according to any one of claims 237 to 274, wherein the subject experiences a reduction in the risk of a major cardiovascular event selected from the group consisting of death, hospitalization due to worsening of the disease, and myocardial infarction.

277. The method according to any one of claims 237 to 275, wherein the treatment further comprises (a) measuring the level of cardiac troponin and / or (b) measuring the level of NT-proBNP or BNP.

278. The method according to any one of claims 237 to 276, further comprising evaluating the NYHA classification score of the subject before and after administration of the therapeutically effective amount of mabacamtene or a pharmaceutically acceptable salt thereof, wherein a decrease in the NYHA score after administration of mabacamtene or a pharmaceutically acceptable salt thereof indicates a reduction in the severity of the disease of the subject.

279. The method according to claim 277, further comprising the step of administering a therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt until the subject moves from NYHA class III to class II, or from class II to class I.

280. The method according to any one of claims 237 to 278, further comprising determining the KCCQ score of the subject before and after administration of the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof, wherein an increase in the KCCQ score after administration of the myosin inhibitor indicates a reduction in the severity of the disease in the subject.

281. The treatment involves the administration of the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof to the subject during exercise, and the maximum oxygen consumption (VO2) of the subject before and after the administration of the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof. ２ ) and / or VE / VCO ２ Further including evaluating the slope, optionally the maximum oxygen consumption (VO2) of the subject. ２ The method according to any one of claims 237 to 279, wherein the number of cases is increasing.

282. The method according to any one of claims 237 to 280, wherein the subject has experienced a reduction in the risk of major cardiovascular events, and the major cardiovascular events are selected from the group consisting of death, hospitalization due to exacerbation of the disease, and myocardial infarction.

283. The method according to any one of claims 237 to 281, wherein the subject experiences a statistically significant reduction in the level(a) cardiac troponin and / or (b) NT-proBNP or BNP.

284. A method of administering mabacamten or a pharmaceutically acceptable salt thereof to a subject suffering from HFpEF, During the first treatment period, administer a first dose of mabacamten or a pharmaceutically acceptable salt thereof to the subject having (1) elevated NT-proBNP levels, elevated cTnT, or elevated cTnI, and (2) a LVEF of 50 or higher; To determine whether the subject responded to mabacamten by observing the level of change in biomarkers in the blood sample and the change in LVEF in the subject at the end of the first treatment period; and If the concentration level of the biomarker in the blood sample decreases and the LVEF does not decrease to less than 50, administer a second dose of mabacamten during the second treatment period. The method, including the method described above.

285. The method according to claim 283, wherein the first dose is 2 mg, 2.5 mg, or 5 mg per day.

286. The method according to claim 283, wherein the second dose is a larger amount per day than the first dose, and the second treatment period is longer than the first treatment period.

287. The method according to claim 283, wherein the biomarker is selected from the group consisting of cTnT, cTnI, NT-proBNP, and BNP.

288. The method according to any one of the prior claims, wherein the myosin modulator or the myosin inhibitor is administered as monotherapy.

289. The method according to any one of claims 1 to 287 or 291 to 398, wherein the myosin modulator or the myosin inhibitor is administered as part of a combination therapy.

290. The aforementioned combination therapies are as follows: Standard of care (SOC) therapy for the aforementioned cardiac condition, or other therapies useful for treating related diseases or disorders; Other therapeutic agents include beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (e.g., angiotensin II receptor blockers), angiotensin receptor neprilysin inhibitors (ARNIs) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (e.g., aldosterone inhibitors, potassium-sparing diuretics such as eplerenone, spironolactone, or canrenone), cholesterol-lowering drugs (e.g., statins), neutral endopeptidase inhibitors (NEPi), and positive inotropic agents (e.g., digoxin, pimobendan, dobutami). Beta-adrenergic receptor agonists such as milrinone, phosphodiesterase (PDE)-3 inhibitors such as milrinone, or calcium sensitizers such as levocimendan), potassium or magnesium, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, vasodilators (e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators), diuretics (e.g., furosemide), warfarin, RAAS inhibitors, antiarrhythmics, anticoagulants, antithrombotic agents, antiplatelet agents, or any combination thereof; A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, Candesartan, Candesartan cilexetil, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177, Erisartan, EMD-66397, EMD-73495, Ep Losartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, Irbesartan, Isoteolin, KRI-1177, KT3-671, KW-3433, Losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874 L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LRB087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, Olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, Salaracin acetate, S-830 7. ARB selected from S-8308, SC-52458, Supplisartan, Salacin, Salmesin, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360, X-6803, Valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155, ZD-8731, or Zolasartan; and ARNI selected from sacubitril / valsartan (Entresto®), or sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin (e.g., Jardiance®), dapagliflozin (e.g., Farxiga®), or sotagliflozin. The method according to claim 288, comprising one or more of the following.

291. The method according to claim 288, wherein the combination therapy comprises treatment with one or more of ARNI (e.g., Entresto®), a beta-blocker, an MRA, and disopyramide.

292. A method for treating a subject suffering from oHCM, comprising administering a myosin modulator to the subject, wherein the subject is eligible for SRT.

293. The method according to claim 291, wherein the treatment comprises administering a therapeutically effective amount of the myosin modulator to the subject.

294. The method according to claim 292, wherein the treatment reduces the likelihood that the subject will receive SRT.

295. The method according to claim 292, wherein the treatment reduces the short-term likelihood that the subject will receive SRT.

296. The method according to claim 292, wherein the treatment eliminates the need for the subject to receive SRT.

297. The method according to claim 291 or 292, wherein the treatment reduces the thickness of the interventricular septum (IVS) wall.

298. The method according to claim 296, wherein the treatment reduces the thickness of the interventricular septum (IVS) wall compared to the IVS thickness before the treatment.

299. The method according to any one of claims 291 to 297, wherein, prior to administration of the myosin modulator, the subject has a ventricular septal (IVS) wall thickness of 13 mm or more and a family history of HCM.

300. The method according to any one of claims 291 to 297, wherein, prior to administration of the myosin modulator, the subject has a ventricular septal (IVS) wall thickness of 15 mm or more.

301. The method according to any one of claims 291 to 299, wherein the subject has severe dyspnea or chest pain prior to the treatment.

302. The method according to any one of claims 291 to 299, wherein the subject has been diagnosed with NYHA class III or IV, or NYHA class II with or without exertional symptoms, prior to the treatment.

303. The method according to any one of claims 291 to 299, wherein the exertional symptoms are exertion-induced syncope or a presyncope state.

304. The method according to any one of claims 291 to 299, wherein the subject has a dynamic LVOT gradient of 50 mmHg or more at rest or induced with septal hypertrophy prior to the treatment.

305. The method according to claim 303, wherein the induction is determined during the Valsalva maneuver or exercise.

306. The method according to any one of claims 291 to 299, wherein the subject has an LVEF of 60% or more before the treatment.

307. The method according to any one of claims 291 to 305, wherein the treatment improves the NYHA classification.

308. The method according to any one of claims 291 to 305, wherein the treatment improves KCCQ.

309. The method according to any one of claims 291 to 307, wherein the myosin modulator is a myosin inhibitor.

310. The method according to claim 308, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

311. The method according to claim 309, wherein the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof is about 2.5 mg to about 15 mg.

312. The method according to claim 309, wherein the therapeutically effective dose is approximately 5 mg to approximately 7.5 mg per day, or approximately 7.5 mg to approximately 15 mg per day.

313. The method according to claim 309, wherein the initial dose is 5 mg per day for at least four weeks prior to dose adjustment.

314. The method according to any one of claims 309 to 312, wherein the therapeutically effective dose is administered once a day for 16 weeks or more.

315. The method according to any one of claims 309 to 312, wherein the therapeutically effective dose is administered once a day for 32 weeks or more.

316. The method according to any one of claims 309 to 312, wherein the therapeutically effective dose is administered once daily for 96 weeks or more.

317. The method according to claim 309, wherein the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof is 5 mg per day for 16 weeks or more.

318. The method according to claim 316, wherein the subject is optionally evaluated for dose adjustment at week 4, week 8, week 12, or week 16.

319. The method according to claim 309, wherein the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof is 5 mg per day for 32 weeks or more.

320. The method according to claim 318, wherein the subject is optionally evaluated for dose adjustment at weeks 4, 8, 12, 16, 20, 24, 28, or 32.

321. The method according to claim 309, wherein the therapeutically effective amount of mabacamten or a pharmaceutically acceptable salt thereof is 5 mg per day for 96 weeks or more.

322. The method according to claim 318, wherein the subject is optionally evaluated for dose adjustment at weeks 4, 8, 12, or 16, 20, 24, 28, or 32, 44, 56, 68, 80, 92, 104, 116, or 128.

323. The method according to any one of claims 317, 319, or 321, wherein each dose adjustment comprises reducing the dose to 2.5 mg or 1 mg per day.

324. The method according to any one of claims 317, 319, or 321, wherein each dose adjustment comprises increasing the dose to 7.5 mg or 15 mg per day.

325. The method according to any one of claims 317, 319, or 321 to 323, wherein the evaluation for the dose adjustment includes evaluation of one or more of the following: vital signs, body weight, NYHA functional classification, adverse events, concomitant medications, physical examination, KCCQ, resting Valsalva test, transthoracic echocardiography, transthoracic echocardiography, post-exercise, accelerometer, application of Holter monitor, single 12-lead ECG, PK sample, blood chemistry and coagulation, cardiac biomarkers, or exploratory biomarkers.

326. The method according to claim 324, wherein the evaluation includes the evaluation of one or more cardiac biomarkers.

327. The method according to claim 325, wherein one or more cardiac biomarkers include NT-proBNP or BNP.

328. The method according to claim 325, wherein one or more cardiac biomarkers include cardiac troponin.

329. The method according to claim 327, wherein the cardiac troponin is cardiac troponin I (cTnI) or high-sensitivity cTnI (hs-cTnI).

330. The method according to claim 327, wherein the cardiac troponin is cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT).

331. The method according to claim 324, wherein the vital signs include body temperature, heart rate (HR), respiratory rate, or blood pressure.

332. The method according to claim 324, wherein the evaluation includes an analysis of the LVOT gradient, left ventricular ejection fraction (LVEF), left ventricular (LV) filling pressure, or left atrial size of the subject.

333. The method according to claim 324, wherein the evaluation includes an evaluation of the change from baseline to 16 weeks in the subject treated with mabacamten compared to the subject treated with placebo.

334. The method according to claim 324, wherein the evaluation includes an evaluation of the change from baseline to week 16 compared to the change from baseline to week 32 of the subject treated with mabacamten.

335. The method according to claim 324, wherein the evaluation includes an assessment of the change from baseline to week 32 in a subject treated with mabacamten, compared to a subject treated with placebo from week 1 to week 16 and then with mabacamten from week 17 to week 32.

336. The method according to any one of claims 331 to 334, wherein the evaluation is an evaluation of the change in the NYHA functional classification, KCCQ-23 score, NT-proBNP or BNP level, cardiac troponin cTnI or cTnT, or LVOT gradient of the subject.

337. The method according to claim 335, wherein the evaluation is an evaluation of NT-proBNP.

338. The method according to claim 335, wherein the cardiac troponin is cardiac troponin I (cTnI) or high-sensitivity cTnI (hs-cTnI).

339. The method according to claim 335, wherein the cardiac troponin is cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT).

340. The method according to any one of the prior claims, wherein the subject is re-evaluated for SRT eligibility at week 16, week 32, week 80, and / or week 128.

341. The method according to any one of claims 324 to 339, wherein the evaluation shows that the method according to any one of claims 291 to 323 reduces the need for the SRT of the subject.

342. The method according to any one of claims 324 to 339, wherein the evaluation shows that the method according to any one of claims 291 to 323 eliminates the need for the SRT of the subject.

343. The method according to any one of the prior claims, wherein the subject is eligible for an SRT consistent with the ACC / AHA 2011 and / or ESC 2014 guidelines.

344. The aforementioned subjects are (a) to (c): (a) NYHA Class III or IV, or NYHA Class II with or without exertional symptoms; (b) A dynamic LVOT gradient of 50 mmHg or greater at rest or induced (i.e., Valsalva maneuver or exercise) accompanied by septal hypertrophy; and (c) A target anterior septal thickness sufficient to allow the individual operator to safely and effectively perform the procedure, The method according to any one of the prior claims, characterized by one or more of the above.

345. The method according to claim 343, wherein the subject is characterized by two or more of (a) to (c).

346. The method according to claim 343, wherein the subject is characterized by all three of (a) to (c).

347. The method according to any one of the prior claims, wherein the subject has elevated troponin levels and / or elevated NT-proBNP or BNP levels.

348. The method according to claim 346, wherein the target has an E / e' greater than 14.

349. The method according to any one of claims 291 to 347, wherein the subject is resistant to treatment with standard treatment for oHCM.

350. The method according to any one of claims 291 to 347, wherein the subject is resistant to treatment of oHCM with beta-blockers, calcium channel blockers, disopyramide, or any combination thereof.

351. The method according to any one of claims 291 to 349, wherein the subject has reached maximum tolerable medical treatment with standard oHCM therapy prior to treatment with a myosin inhibitor, mabacamten or a pharmaceutically acceptable salt thereof, remains symptomatic NYHA class III or IV, and has an LVOT gradient of 50 mmHg or more.

352. The method according to any one of claims 291 to 349, wherein the subject has reached maximum tolerable medical treatment with a beta-blocker, a calcium channel blocker, and / or disopyramide prior to treatment with a myosin inhibitor or mabacamten or a pharmaceutically acceptable salt thereof, remains symptomatic NYHA class III or IV, and has an LVOT gradient of 50 mmHg or greater.

353. The method according to any one of claims 291 to 351, wherein the subject receives adjunctive therapy, including treatment with standard treatment for oHCM, in the course of treatment with the myosin inhibitor or mabacamten or a pharmaceutically acceptable salt thereof.

354. The method according to any one of claims 291 to 351, wherein the subject receives adjunctive therapy comprising a beta-blocker, a calcium channel blocker, disopyramide, or any combination thereof, in the course of treatment with the myosin inhibitor, or mabacamten or a pharmaceutically acceptable salt thereof.

355. The method according to any one of claims 291 to 353, wherein the subject is classified as NYHA degree IV.

356. The method according to any one of claims 291 to 354, wherein the oHCM is symptomatic oHCM.

357. The method according to claim 324, wherein the evaluation includes an analysis of the LVOT gradient and / or LVEF.

358. The method according to claim 356, comprising increasing the dose of mabacamten when the LVOT gradient of the subject exceeds 30 mmHg and the LVEF of the subject is 50% or more.

359. The method according to any one of claims 291 to 357, wherein the patient to be treated meets the selection and exclusion criteria of Example 6.

360. The method according to claim 293, wherein reducing the likelihood of a subject receiving SRT includes (1) a reduction in the patient's desire to continue SRT, and / or (2) a resulting change in SRT guideline eligibility that makes the patient ineligible to receive SRT.

361. The method according to any one of claims 293, 294, or 359, wherein the change in likelihood is based on the likelihood assessment at baseline compared to the likelihood assessment at week 16 and / or week 32, and the reduction from baseline in the likelihood of the subject receiving SRT is achieved by week 16 and maintained at week 32.

362. The method according to any one of the prior claims, wherein the myosin modulator or the myosin inhibitor is mabacamtene, and the mabacamtene is a form A crystal of mabacamtene.

363. A method for treating or alleviating shortness of breath in a patient diagnosed with symptomatic obstructive humerus, comprising administering a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient once daily for more than 21 weeks.

364. The method according to claim 362, wherein shortness of breath is measured by a patient-reported questionnaire.

365. The method according to claim 363, wherein the questionnaire comprises two or more questions relating to the patient's shortness of breath symptoms.

366. The method according to claim 364, wherein the questionnaire is HCMSQ-SoB.

367. The method according to any one of claims 362 to 365, wherein the therapeutically effective dose is approximately 2.5 mg to approximately 15 mg per day.

368. The method according to any one of claims 362 to 366, wherein mabacamten is administered for at least 30 weeks.

369. The method according to any one of claims 362 to 367, wherein the patient has a LVEF of more than 50%.

370. The method according to any one of claims 362 to 368, wherein the therapeutically effective dose causes the trough plasma concentration of mabacamten in the patient to be about 350 to about 700 ng / mL.

371. The method according to any one of claims 362 to 369, wherein the therapeutically effective dose causes the patient's post-exercise LVOT gradient to be less than approximately 50 mmHg or less than approximately 30 mmHg.

372. A method for improving the quality of life for patients diagnosed with symptomatic obstructive HCM, The treatment comprises administering a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient for at least 30 weeks. The method wherein the improvement in the patient's quality of life is measured by an improvement of at least 6 points in the patient's KCCQ score compared to before treatment with mabacamten or a pharmaceutically acceptable salt thereof.

373. The method according to claim 371, wherein the KCCQ score is based on using one or all of KCCQ-CSS, KCCQ-OSS, or KCCQ-TSS.

374. The method according to claim 371 or 372, wherein the improvement in quality of life is further measured by the improvement in shortness of breath.

375. The method according to claim 373, wherein improvement in shortness of breath is determined by a questionnaire consisting of two or more questions.

376. The method according to claim 373, wherein improvement in shortness of breath is determined by the HCMSQ-SoB score.

377. The method according to claim 371, wherein the patient achieves a 6-point improvement in the KCCQ score.

378. The method according to any one of claims 371 to 376, wherein the therapeutically effective dose is approximately 2.5 mg to approximately 15 mg per day.

379. The method according to any one of claims 371 to 377, wherein the patient has a LVEF of more than 50%.

380. The method according to any one of claims 371 to 378, wherein the therapeutically effective dose causes the trough plasma concentration of mabacamten in the patient to be about 350 to about 700 ng / mL.

381. The method according to any one of claims 371 to 379, wherein the therapeutically effective dose causes the patient's post-exercise LVOT gradient to be less than approximately 30 mmHg or less than approximately 50 mmHg.

382. A method for treating symptomatic obstructive cholangiopathic disease in patients who require treatment for it, Administer mabacamten or a pharmaceutically acceptable salt thereof to the patient at an initial dose of approximately 2.5 to 5 mg per day; and This includes setting the initial dose to a second dose of approximately 2.5 to 15 mg per day, The aforementioned patient: Improvement of at least 1.5 mL / kg / min in maximum oxygen consumption (pVO2), and a reduction of 1 degree or more in the NYHA functional classification; Improvement in pVO2 of 3.0 mL / kg / min or more without deterioration of NYHA functional classification; Improvement in the maximum LVOT gradient after exercise; At least one improvement in the NYHA functional classification; Improvement of pVO2; Improvement in KCCQ score; Improvement in HCMSQ score; The maximum LVOT gradient after exercise is <50 mmHg; The maximum LVOT gradient after exercise is <30 mmHg; Improvement of NT-proBNP level; and Improvement of hs-cTnI levels, The method for achieving one or more of the above.

383. The aforementioned patient: Improvement in EuroQol 5-Dimensional 5-Level Questionnaire scores; Improvement in questionnaire scores regarding work productivity and activity impairment; Improvement in the overall patient impression score and the overall patient impression-severity score; and Improvement of daily step count and other accelerometer parameters, The method according to claim 381, which achieves one or more of the following.

384. The method according to claim 381 or 382, ​​comprising setting the starting dose such that the trough plasma concentration of mabacamten in the patient reaches approximately 350 to approximately 700 ng / mL.

385. The method according to claim 383, comprising setting the starting dose such that the trough plasma concentration of mavacamten in the patient reaches about 350 to about 700 ng / mL, and the Valsalva LVOT gradient in the patient reaches less than about 30 mmHg.

386. The method according to any one of claims 381 to 384, wherein the initial dose is 2.5 or 5 mg per day.

387. The method according to any one of claims 381 to 385, wherein the second dose is 2.5, 5, 10, or 15 mg per day.

388. The method according to any one of claims 381 to 386, wherein mabacamten is administered daily for at least about 30 weeks.

389. The patient being treated, (a) oHCM classified as NYHA II or NYHA III, (b) Maximum LVOT gradient greater than 50 mmHg as assessed by echocardiography at rest, after the Valsalva maneuver, or after exercise, and (c) LVEF exceeding 55% The method according to any one of claims 381 to 387, comprising:

390. The method according to any one of claims 381 to 388, wherein the patient satisfies the selection and / or exclusion criteria set out in Table 7.0 of Example 7.

391. The method according to any one of claims 381 to 388, wherein setting the initial dose to a second dose of approximately 2.5 to approximately 15 mg per day includes setting the initial dose to a second dose of 2.5 mg per day when the patient's Valsalva LVOT gradient is less than 20 mmHg.

392. A method for treating symptomatic obstructive cholangiopathic disease in patients who require treatment for it, Administer mabacamten or a pharmaceutically acceptable salt thereof to the patient at a starting dose of approximately 2.5 to 5 mg per day; This includes setting the initial dose to a second dose of approximately 2.5 to 15 mg per day so that the patient's Valsalva LVOT gradient reaches less than approximately 30 mmHg. The aforementioned patient: Improvement of at least 1.5 mL / kg / min in maximum oxygen consumption (pVO2), and a reduction of 1 degree or more in the NYHA functional classification; Improvement in pVO2 of 3.0 mL / kg / min or more without deterioration of NYHA functional classification; Improvement in the maximum LVOT gradient after exercise; At least one improvement in the NYHA functional classification; Improvement of pVO2; Improvement in KCCQ score; Improvement in HCMSQ score; The maximum LVOT gradient after exercise is <50 mmHg; The maximum LVOT gradient after exercise is <30 mmHg; Improvement of NT-proBNP level; and Improvement of hs-cTnI levels, The method for achieving one or more of the above.

393. The aforementioned patient: Improvement in EuroQol 5-Dimensional 5-Level Questionnaire scores; Improvement in questionnaire scores regarding work productivity and activity impairment; Improvement in the overall patient impression score and the overall patient impression-severity score; and Improvement of daily step count and other accelerometer parameters, The method according to claim 391, which achieves one or more of the following.

394. The method according to claim 391 or 392, comprising setting the starting dose such that the patient's Valsalva LVOT gradient reaches less than about 30 mmHg and the patient's trough plasma concentration of mavacamten reaches about 350 to about 700 ng / mL.

395. The method according to any one of claims 391 to 393, wherein the starting dose is 2.5 or 5 mg per day.

396. The method according to any one of claims 391 to 394, wherein the second dose is 2.5, 5, 10, or 15 mg per day.

397. The method according to any one of claims 391 to 395, wherein mabacamten is administered daily for at least about 30 weeks.

398. The method according to any one of claims 391 to 396, wherein the patient to be treated meets the selection and / or exclusion criteria in Table 7.0 of Example 7.

399. The method according to any one of the prior claims, wherein the mabacamten is a type A crystal of mabacamten.

400. The method according to any one of claims 391 to 398, wherein setting the initial dose to a second dose of about 2.5 to about 15 mg per day so that the patient's Valsalva LVOT gradient reaches less than about 30 mmHg is further comprising setting the initial dose to a second dose of 2.5 mg per day when the patient's Valsalva LVOT gradient is less than 20 mmHg.

401. A method for treating HCM in patients who require treatment for it, (a) administering a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient once daily; (b) If the ejection fraction of the patient falls below the threshold ejection fraction, the administration of mabacamten or a pharmaceutically acceptable salt thereof is temporarily discontinued; (c) Resuming administration of a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient once daily, The method, including the method described above.

402. The method according to claim 400, wherein the threshold ejection fraction is 50%.

403. (b) The method according to claim 400 or 401, further comprising: (b) If the ejection rate of the patient falls below the threshold ejection rate, temporarily discontinuing the administration of mabacamten or a pharmaceutically acceptable salt thereof for about 4 to about 6 weeks, or until the ejection rate returns to above 50%.

404. (c) The method according to any one of claims 400 to 402, comprising restarting administration of a therapeutically effective dose of mabacamten or a pharmaceutically acceptable salt thereof to the patient once daily for at least about four weeks.

405. The method according to any one of claims 400 to 403, wherein the therapeutically effective dose is approximately 2.5 mg to approximately 15 mg per day.

406. The therapeutically effective dose is such that the trough plasma concentration of mabacamten in the patient is approximately 350 to approximately 700 ng / mL. and / or The method according to any one of claims 399 to 403, wherein the therapeutically effective dose causes the patient's post-exercise LVOT gradient to be less than approximately 50 mmHg or less than approximately 30 mmHg.

407. After resuming administration according to step (c), the patient: Improvement of at least 1.5 mL / kg / min in maximum oxygen consumption (pVO2), and a reduction of 1 degree or more in the NYHA functional classification; Improvement in pVO2 of 3.0 mL / kg / min or more without deterioration of NYHA functional classification; Improvement in the maximum LVOT gradient after exercise; At least one improvement in the NYHA functional classification; Improvement of pVO2; Improvement in KCCQ score; Improvement in HCMSQ score; The maximum LVOT gradient after exercise is <50 mmHg; The maximum LVOT gradient after exercise is <30 mmHg; Improvement of NT-proBNP level; and Improvement of hs-cTnI levels, The method according to any one of claims 400 to 405, which achieves one or more of the above.

408. The aforementioned patient: Improvement in EuroQol 5-Dimensional 5-Level Questionnaire scores; Improvement in questionnaire scores regarding work productivity and activity impairment; Improvement in the overall patient impression score and the overall patient impression-severity score; and Improvement of daily step count and other accelerometer parameters, The method according to claim 405, which achieves one or more of the following.

409. The method according to any one of claims 362 to 406, wherein the patient achieves an improvement in the maximum LVOT gradient after exercise and an improvement of at least one degree in the NYHA functional classification.

410. The method according to claim 407, wherein the patient achieves an exercise-induced maximum LVOT gradient of less than 50 mmHg and an improvement of at least 1 degree in the NYHA functional classification.

411. The method according to claim 408, wherein the patient achieves a post-exercise maximum LVOT gradient of less than 30 mmHg and an improvement of at least 1 degree in the NYHA functional classification.

412. A method for treating hypertrophic cardiomyopathy (HCM) in a patient with a low metabolic form of mabacamten, Administer a starting dose of 2.5 mg of mabacamten per day to the subject; and The dosage for subsequent doses is determined based on the pharmacokinetic measurement values ​​and / or LVOT gradient of the subject. The method, including the method described above.

413. The method according to claim 410, wherein the subsequent dose is based on the plasma concentration of the target mabacamten.

414. The method according to claim 410, wherein the subsequent dose is based on the body weight of the subject.

415. The method according to claim 410, wherein the subsequent dose is based on the plasma concentration of the subject mabacamten and the subject's body weight.

416. The method according to any one of claims 410 to 413, wherein the subsequent dose is 1 mg.

417. The method according to any one of claims 410 to 413, wherein the subsequent dose is 5 mg, 10 mg, or 15 mg.

418. The method according to any one of claims 410 to 415, wherein the low metabolite of mabacamten has the CYP2C19 low metabolite genotype.

419. The low metabolic form of the aforementioned mabacamten is CYP2C19 ＊ 2 / ＊ 2. ＊ 2 / ＊ 3, or ＊ 3 / ＊ The method according to claim 416, having three genotypes.

420. The method according to any one of claims 410 to 417, wherein the low metabolic type of mabacamten is of Asian descent.

421. The method according to claim 418, wherein the low metabolic type of mabacamten is of Japanese descent.

422. The method according to any one of claims 410 to 419, wherein the subsequent dose administration maintains the plasma concentration of the target mabacamten at 350 to 700 ng / mL.

423. The method according to any one of claims 410 to 419, wherein if the plasma concentration of the target mabacamten exceeds 700 ng / mL after administration of the initial dose, the subsequent dose is approximately 1 mg.

424. The method according to any one of claims 410 to 419, wherein, after administration of the initial dose, the plasma concentration of the mavacamten in the subject falls below 350 ng / mL, and the Valsalva gradient in the subject after administration of the initial dose is 30 mmHg or more, the subsequent dose is approximately 5 mg.

425. The method according to any one of claims 410 to 422, wherein the HCM is an occlusive HCM (oHCM).

426. The method according to any one of claims 410 to 423, which reduces the risk of adverse events in the subject who is a low metabolite of mabacamten.

427. The method according to any one of claims 410 to 424, which reduces the risk of contractile dysfunction in the subject who is a low metabolite of mabacamten.

428. A method for treating HCM in subjects of Asian descent, Administer a starting dose of 2.5 mg of mabacamten per day to the subject; and The dosage for subsequent doses is determined based on the pharmacokinetic measurement values ​​and / or LVOT gradient of the subject. The method, including the method described above.

429. The method according to claim 426, wherein the subsequent dose is based on the plasma concentration of the target mabacamten.

430. The method according to claim 426, wherein the subsequent dose is based on the body weight of the subject.

431. The method according to claim 426, wherein the subsequent dose is based on the plasma concentration of the subject mabacamten and the subject's body weight.

432. The method according to any one of claims 426 to 429, wherein the subsequent dose is 1 mg.

433. The method according to any one of claims 426 to 429, wherein the subsequent dose is 5 mg, 10 mg, or 15 mg.

434. The method according to any one of claims 426 to 431, wherein the subsequent dose administration maintains the plasma concentration of the target mabacamten at 350 to 700 ng / mL.

435. The method according to any one of claims 426 to 432, wherein the subsequent dose is approximately 1 mg when the weight of the subject is less than 50 kg or less than 45 kg.

436. The method according to any one of claims 426 to 433, wherein if the weight of the subject exceeds 70 kg, the subsequent dose is approximately 5 mg.

437. The method according to any one of claims 426 to 434, wherein the HCM is an occlusive HCM (oHCM).

438. The method according to any one of claims 426 to 435, wherein the Asian person is of Japanese descent.

439. The method according to any one of claims 426 to 435, wherein the Asian person is of Japanese, Chinese, Thai, Korean, Filipino, Indonesian, and Vietnamese descent.

440. Purified crystalline mabacamtene, characterized as form A, substantially free from other crystalline or amorphous forms of mabacamtene.

441. The purified crystalline form of mabacamtene according to claim 438, wherein the mabacamtene has a chiral purity of at least 95%, or at least 99%.

442. The purified crystalline form according to claim 438, having an X-ray powder diffraction pattern comprising a peak at 18.8°²θ ± 0.1°²θ and at least four peaks selected from the group consisting of 10.0, 11.7, 14.6, 15.7, 16.2, 17.5, 20.0, 22.5, 25.7, 26.2 and 29.2°²θ, with a variation of ±0.1°²θ.

443. The purified crystalline form according to claim 438, having an X-ray powder diffraction pattern comprising a peak at 18.8°²θ ± 0.1°²θ and at least eight peaks selected from the group consisting of 10.0, 11.7, 14.6, 15.7, 16.2, 17.5, 20.0, 22.5, 25.7, 26.2 and 29.2°²θ, with a variation of ±0.1°²θ.

444. The purified crystalline form according to claim 438, having an X-ray powder diffraction pattern that includes peaks at 10.0, 11.7, 14.6, 15.7, 16.2, 17.5, 18.8, 20.0, 22.5, 25.7, 26.2 and 29.2°², with a variation of ±0.1°²θ.

445. Simple Bravais grid and P2 １ 2 １ 2 １ A refined crystalline form according to any one of claims 438 to 442, having an orthorhombic crystal system with a space group.

446. The aforementioned crystal morphology has unit cell parameters at approximately 25°C: a = 9.47 Å, b = 12.09 Å, c = 12.70 Å, α＝９０．００°、 β = 90.00°, and γ = 90.00° A purified crystalline form according to any one of claims 438 to 443, having the following characteristics.

447. The purified crystalline form according to any one of claims 438 to 444, wherein at least 99.5% by weight is of type A.

448. A method for producing a crystalline solid according to any one of claims 438 to 445, comprising recrystallizing a compound in ethanol or an ethanol / water mixture to form a crystalline solid of type A.

449. The method according to claim 446, further comprising adding a type A seed crystal.

450. The method according to claim 446 or 447, further comprising stirring the slurry of the crystalline solid at an internal temperature of about 5°C to about 10°C for about 24 hours.

451. The method according to any one of claims 446 to 448, further comprising washing the solid recrystallization product with methyl tert-butyl ether.

452. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a crystalline solid of type A as described in any one of claims 438 to 445.

453. The pharmaceutical composition according to claim 450, comprising essentially a crystalline solid of type A as described in any one of the prior claims.

454. The method according to any one of the prior claims, wherein the myosin modulator, the myosin inhibitor, or mabacamten is a form A crystal of mabacamten.

455. The method according to claim 452, wherein the A-type crystals of mabacamten are the purified crystalline form described in any one of claims 438 to 445.

456. A method for treating symptomatic oHCM in patients who require treatment for it, Administer the patient a starting dose of 5 mg of mabacamten or a pharmaceutically acceptable salt thereof per day for at least 4 weeks; To evaluate the LVOT gradient of the patient using the Valsalva maneuver and determine the first Valsalva gradient; If the first Valsalva gradient is less than 20 mmHg, reduce the dose of mabacamten or a pharmaceutically acceptable salt thereof to 2.5 mg per day; Continue administration of mabacamten or a pharmaceutically acceptable salt thereof; To evaluate the patient's LVOT gradient using the Valsalva maneuver and determine a second Valsalva gradient; and If the second Valsalva gradient exceeds 30 mmHg, increase the dose from 2.5 mg to 5 mg per day, or from 5 mg to 10 mg per day. The method, including the method described above.

457. The method according to claim 454, wherein the first Valsalva gradient is measured approximately 4 to 6 weeks after administration.

458. The method according to claim 454 or 455, wherein the second Valsalva gradient is measured approximately 12 weeks after administration.

459. The method according to any one of claims 454 to 456, further comprising evaluating the patient's LVEF before administration, wherein the administration of the starting dose is initiated when the LVEF is 55% or greater.

460. The method according to any one of claims 454 to 456, further comprising evaluating the patient's LVEF during administration and temporarily discontinuing administration if the patient's LVEF is less than 50%.

461. The method according to claim 458, wherein administration is discontinued for 4 to 6 weeks or until the LVEF returns to 50% or more.

462. The method according to any one of claims 454 to 459, wherein if the second Valsalva gradient exceeds 30 mmHg and the patient has a LVEF of 55% or more, the dose is increased from 2.5 mg to 5 mg per day, or from 5 mg to 10 mg per day.

463. To evaluate the LVOT gradient of the patient using the Valsalva maneuver and determine a third Valsalva gradient, and If the third Valsalva gradient exceeds 30 mmHg, increase the dose from 2.5 mg to 5 mg per day, from 5 mg to 10 mg per day, or from 10 mg to 15 mg per day. The method according to any one of claims 454 to 459, further comprising:

464. The method according to claim 461, wherein if the third Valsalva gradient exceeds 30 mmHg and the patient has a LVEF of 55% or more, the dose is increased from 2.5 mg to 5 mg per day, from 5 mg to 10 mg per day, or from 10 mg to 15 mg per day.

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