JPWO2021092598A5

JPWO2021092598A5 -

Info

Publication number: JPWO2021092598A5
Application number: JP2022526496A
Authority: JP
Publication date: 2024-01-09

Claims

A pharmaceutical composition comprising a myosin modulator for use in the treatment of a subject suffering from obstructive hypertrophic cardiomyopathy ( oHCM ) , said subject being eligible for septal reduction therapy ( SRT ) . Pharmaceutical composition .

The treatment reduces the likelihood that the subject will receive SRT, reduces the short-term likelihood that the subject will receive SRT, eliminates the need for the subject to receive SRT, and/or septal reduction therapy for the subject. 2. The composition of claim 1 , which reduces the need for .

2. The composition of claim 1 , wherein the treatment reduces interventricular septal (IVS) wall thickness.

Before treatment , the subject has an interventricular septal (IVS) wall thickness of 13 mm or more and has a family history of HCM , and/or the subject has an interventricular septal (IVS) wall thickness of 15 mm or more. The composition according to any one of claims 1 to 3 , having the following.

Prior to said treatment, said subject has been diagnosed with NYHA grade III or IV, or NYHA grade II with or without symptoms on exertion, and has a dynamic pressure of 50 mm Hg or more at rest or induced with septal hypertrophy. The composition according to any one of claims 1 to 4 , having an LVOT gradient and an LVEF of 60% or more .

Composition according to any one of claims 1 to 5 , wherein the treatment improves NYHA classification and/or improves KCCQ .

The composition according to any one of claims 1 to 6 , wherein the myosin modulator is a myosin inhibitor.

8. The composition according to claim 7 , wherein the myosin inhibitor is mavacamten or a pharmaceutically acceptable salt thereof.

9. The composition of claim 8 , wherein the mavacamten or pharmaceutically acceptable salt thereof is in a therapeutically effective amount from about 2.5 mg to about 15 mg.

10. The composition of claim 8 or 9 , wherein the therapeutically effective amount is administered once daily for 16 weeks or more, 32 weeks or more, or 96 weeks or more .

9. The composition of claim 8 , wherein the therapeutically effective amount of mavacamten or a pharmaceutically acceptable salt thereof is 5 mg per day for 16 weeks or more.

12. The composition of claim 11 , wherein the subject is evaluated for dose adjustment at week 4, week 8, week 12, or week 16.

The evaluation for the dose adjustment includes vital signs, weight, NYHA functional class, adverse events, concomitant medications, physical examination, KCCQ, resting Valsalva, transthoracic echocardiogram, transthoracic echocardiogram, post-exercise, accelerometer, 13. The composition of claim 12, comprising assessment of any one or more of the following: application of a Holter monitor, single 12-lead ECG, PK sample, blood chemistry and coagulation, cardiac biomarkers, or exploratory biomarkers.

14. The composition of claim 13 , wherein the assessment comprises assessment of one or more cardiac biomarkers, the one or more cardiac biomarkers comprising NT-proBNP or BNP, or cardiac troponin .

14. The composition of claim 13 , wherein the assessment comprises an analysis of the subject's LVOT gradient, left ventricular ejection fraction (LVEF), left ventricular (LV) filling pressure, or left atrial size.

The said evaluation is
(a) assessing the change from baseline to week 16 in said subjects treated with mavacamten compared to said subjects treated with placebo;
(b) assessing the change from baseline to week 16 compared to the change from baseline to week 32 in said subject treated with mavacamten; and
(c) Week 32 from baseline for said subject treated with mavacamten compared to said subject treated with placebo from week 1 to week 16 and then treated with mavacamten from week 17 to week 32. Evaluation of the amount of change up to;
14. The composition of claim 13 , comprising one or more of :

17. The method according to claim 15 or 16 , wherein the evaluation is to evaluate the amount of change in NYHA functional class, KCCQ-23 score, NT-proBNP or BNP level, cardiac troponin cTnI or cTnT, or LVOT slope of the subject. Composition .

18. The composition of any one of claims 1-17 , wherein the subject is re-evaluated for SRT eligibility at 16 weeks, 32 weeks, 80 weeks, and/or 128 weeks.

19. The composition of any one of claims 13-18 , wherein said assessment indicates that said subject reduces or eliminates the need for SRT.

Composition according to any one of claims 1 to 19 , wherein the subject is eligible for SRT consistent with ACC/AHA2011 and/or ESC2014 guidelines.

The target is (a) to (c):
(a) NYHA grade III or IV, or NYHA grade II with or without symptoms on exertion;
(b) a dynamic LVOT slope of 50 mm Hg or more at rest or induced (i.e., Valsalva or exercise) with septal hypertrophy; and (c) sufficient to safely and effectively perform the procedure in the judgment of the individual operator. target anterior septal thickness,
Composition according to any one of claims 1 to 20 , characterized by one or more of:

22. The composition of any of claims 1-21 , wherein the subject has elevated troponin levels, elevated NT-proBNP or BNP levels , and/or E/e' greater than 14 .

12. The subject is refractory to treatment with standard treatments for oHCM, and wherein the treatment with standard treatments for oHCM comprises treatment with a beta blocker, a calcium channel blocker, disopyramide, or any combination thereof. The composition according to any one of items 1 to 22 .

The subject has reached maximum tolerated medical treatment with standard of care oHCM therapy and has symptomatic NYHA grade III or grade IV prior to treatment with a myosin inhibitor, mavacamten or a pharmaceutically acceptable salt thereof. 24. The composition according to any one of claims 1 to 23 , wherein the composition remains intact and has an LVOT slope of 50 mmHg or more.

The subject receives adjunctive therapy during treatment with the myosin inhibitor, or mavacamten or a pharmaceutically acceptable salt thereof, including treatment with a standard of care for oHCM , where the treatment with the standard of care includes a beta-blocker, 23. A composition according to any one of claims 1 to 22 , comprising treatment with a calcium channel blocker, disopyramide, or any combination thereof .

Composition according to any one of claims 1 to 25 , wherein the subject is classified as NYHA grade IV.

Reducing the likelihood that a subject will receive SRT may result in (1) a reduced patient's desire to continue SRT, and/or (2) a resulting change in SRT guideline eligibility that may result in said patient receiving SRT. 3. The composition of claim 2 , comprising becoming ineligible to receive.

a reduction from baseline in the likelihood that the subject will receive SRT, where the change in likelihood is based on the likelihood assessment at baseline compared to the likelihood assessment at 16 and/or 32 weeks; 28. The composition of any one of claims 2 or 27 , wherein is achieved by week 16 and maintained at week 32.