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US-12616697-B2 - Methods of treatment with myosin modulator

US12616697B2US 12616697 B2US12616697 B2US 12616697B2US-12616697-B2

Abstract

Methods of treatment comprising administering a therapeutically effective amount of a myosin modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof and diagnostic methods useful in connection with those treatments are disclosed herein. Treatments performed in the absence of beta blocker therapy or with reduced beta blocker therapy are also disclosed.

Inventors

  • Amy Sehnert
  • Jay M. Edelberg

Assignees

  • MyoKardia, Inc.

Dates

Publication Date
20260505
Application Date
20210826

Claims (20)

  1. 1 . A method of treating a patient having cardiac hypercontractility, impaired cardiac relaxation and/or left ventricular hypertrophy, wherein the patient is undergoing β blocker therapy, the method comprising: discontinuing the β blocker therapy or reducing the amount of β blocker therapy; and administering to the patient a therapeutically effective amount of a myosin inhibitor; wherein the patient achieves an improvement in pVO 2 of at least about 2.2 mL/kg/min.
  2. 2 . A method of treating a patient having cardiac hypercontractility, impaired cardiac relaxation and/or left ventricular hypertrophy, wherein the patient is undergoing β blocker therapy, the method comprising: discontinuing the β blocker therapy or reducing the amount of β blocker therapy; and administering to the patient a therapeutically effective amount of a myosin inhibitor; wherein the patient achieves (i) an improvement of at least 1.5 mL/kg/min in pVO 2 and a reduction of 1 or more NYHA Class, or (ii) an improvement of at least 3.0 mL/kg/min in pVO 2 with no worsening in NYHA Class.
  3. 3 . A method of treating a patient having cardiac hypercontractility, impaired cardiac relaxation and/or left ventricular hypertrophy, wherein the patient is undergoing β blocker therapy, the method comprising: discontinuing the β blocker therapy or reducing the amount of β blocker therapy; and administering to the patient a therapeutically effective amount of a myosin inhibitor; wherein the patient has one or more of: an ejection fraction >55% prior to administration of the myosin inhibitor; an E/e′>14 prior to administration of the myosin inhibitor; and a left ventricular wall thickness ≥15 mm or ≥13 mm with family history of HCM prior to administration of the myosin inhibitor.
  4. 4 . A method of treating a patient having cardiac hypercontractility, impaired cardiac relaxation and/or left ventricular hypertrophy, wherein the patient is undergoing β blocker therapy, the method comprising: discontinuing the β blocker therapy or reducing the amount of β blocker therapy; and administering to the patient a therapeutically effective amount of a myosin inhibitor; wherein the patient with cardiac hypercontractility has ejection fraction of >55% and evidence of oHCM, HCM and/or heart failure symptoms prior to beginning the first treatment phase.
  5. 5 . The method of claim 1 , wherein the patient is suffering from oHCM, and wherein the method comprises discontinuing the β blocker therapy.
  6. 6 . The method of claim 5 , wherein the myosin inhibitor is mavacamten or a pharmaceutically acceptable salt thereof.
  7. 7 . The method of claim 5 , wherein the myosin inhibitor is mavacamten.
  8. 8 . The method of claim 5 , wherein the myosin inhibitor is: or a pharmaceutically acceptable salt thereof.
  9. 9 . The method of claim 5 , wherein the myosin inhibitor is:
  10. 10 . The method of claim 2 , wherein the patient is suffering from oHCM, and wherein the method comprises discontinuing the β blocker therapy.
  11. 11 . The method of claim 10 , wherein the myosin inhibitor is mavacamten or a pharmaceutically acceptable salt thereof.
  12. 12 . The method of claim 10 , wherein the myosin inhibitor is mavacamten.
  13. 13 . The method of claim 10 , wherein the myosin inhibitor is: or a pharmaceutically acceptable salt thereof.
  14. 14 . The method of claim 10 , wherein the myosin inhibitor is:
  15. 15 . The method of claim 3 , wherein the patient is suffering from oHCM, and wherein the method comprises discontinuing the β blocker therapy.
  16. 16 . The method of claim 15 , wherein the myosin inhibitor is mavacamten or a pharmaceutically acceptable salt thereof.
  17. 17 . The method of claim 15 , wherein the myosin inhibitor is mavacamten.
  18. 18 . The method of claim 15 , wherein the myosin inhibitor is: or a pharmaceutically acceptable salt thereof.
  19. 19 . The method of claim 15 , wherein the myosin inhibitor is:
  20. 20 . The method of claim 4 , wherein the patient is suffering from oHCM, and wherein the method comprises discontinuing the β blocker therapy.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a 35 U.S.C. § 371 United States National Phase Application of PCT Application No. PCT/US2021/047711, filed Aug. 26, 2021 which claims priority from U.S. Provisional Patent Application 63/072,094, filed Aug. 28, 2020. The disclosures of those priority applications are incorporated by reference herein in their entirety. TECHNICAL FIELD The present disclosure relates to methods of treatment comprising administering a therapeutically effective amount of a myosin modulator or a pharmaceutically acceptable salt thereof to a subject in need thereof and diagnostic methods useful in connection with those treatments. The disclosure also relates to treatment performed in the absence of beta blocker therapy or with reduced beta blocker therapy. BACKGROUND Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease in which excessive contraction of the heart muscle and reduced left ventricle filling capacity can lead to the development of debilitating symptoms and cardiac dysfunction. HCM is estimated to affect one in every 500 people. The most frequent cause of HCM is mutations in the proteins of the cardiac sarcomere. In approximately two-thirds of HCM subjects, the path followed by blood exiting the heart, known as the left ventricular outflow tract (LVOT), becomes obstructed by the enlarged and diseased muscle, restricting the flow of blood from the heart to the rest of the body (obstructive HCM). In other subjects, the thickened heart muscle does not block the LVOT, and their disease is driven by diastolic impairment due to the enlarged and stiffened heart muscle (non-obstructive HCM). In either obstructive or non-obstructive HCM subjects, exertion can result in fatigue or shortness of breath, interfering with a subject's ability to participate in activities of daily living. HCM has also been associated with increased risks of atrial fibrillation, stroke, heart failure and sudden cardiac death. Mavacamten is a novel, oral, allosteric modulator of cardiac myosin being developed for the treatment of hypertrophic cardiomyopathy (HCM). This therapy is intended to reduce cardiac muscle contractility by inhibiting the excessive myosin-actin cross-bridge formation that underlies the excessive contractility, left ventricular hypertrophy and reduced compliance characteristics of HCM. Mavacamten is currently being evaluated in multiple clinical trials for the treatment of obstructive and non-obstructive HCM. A pivotal Phase 3 clinical trial, known as EXPLORER-HCM, is being conducted in subjects with symptomatic, obstructive HCM and Additionally, a Phase 2 clinical trial known as MAVERICK-HCM is being conducted in subjects with symptomatic, non-obstructive HCM (nHCM); and two long term follow-up studies are also ongoing, the PIONEER open-label extension study of obstructive HCM subjects from Phase 2 PIONEER trial and the MAVA-LTE, an extension study for subjects who have completed either EXPLORER-HCM or MAVERICK-HCM. Mavacamten is the first myosin inhibitor to enter into clinical trials. Due to observations unfolding in the clinical trials with mavacamten and with mavacamten and other myosin inhibitors in the pre-clinical setting, new insights into how myosin inhibitors can be used beneficially to impact the disease state of HCM and other diseases will be provided in this application. SUMMARY Provided herein is a method of treating a patient having cardiac hypercontractility, impaired cardiac relaxation and/or left ventricular hypertrophy, wherein the patient is undergoing β blocker therapy, the method comprising: administering to the patient a therapeutically effective amount of a myosin inhibitor during a first treatment phase during which the patient also receives β blocker therapy; andcontinuing to administer to the patient a therapeutically effective amount of a myosin inhibitor during a second treatment phase during which the patient either (a) does not receive β blocker therapy, or (b) receives a reduced amount of β blocker therapy. In some embodiments, the patient does not receive β blocker therapy during the second treatment phase. In some embodiments, the patient receives a reduced amount of β blocker therapy during the second treatment phase. In some embodiments, the reduced amount of β blocker therapy comprises a smaller dose of a β blocker. In some embodiments, the reduced amount of β blocker therapy comprises a less frequent dose of a β blocker. In some embodiments, the method comprises transitioning from the first treatment phase to the second treatment phase when the patient achieves a therapeutically effective steady state of the myosin inhibitor. In some embodiments, the steady state is achieved when the patient achieves a dose amount with no significant change in efficacy. In some embodiments, the steady state is achieved in the time period of about 4 to 5 times the half life of the myosin inhibitor following administration of the myosin inh