Methods of administering myosin inhibitors

Abstract

Methods of administering a myosin inhibitor to a patient and related risk mitigation methods, including distribution control, are described herein. The methods disclosed herein provide for safe administration of Mavakaii and other myosin inhibitors and mitigate the risk of heart failure due to systolic dysfunction.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 335,028, filed on April 26, 2022; U.S. Provisional Application No. 63 / 335,209, filed on April 26, 2022; and U.S. Provisional Application No. 63 / 336,254, filed on April 28, 2022, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to methods of administering myosin inhibitors to patients and associated risk mitigation methods including dispensing controls. Background Art

[0004] Hypertrophic cardiomyopathy (HCM) is a heart disease caused by an excessive number of myosin-actin cross-bridges, which leads to excessive contractility and impaired relaxation and compliance. Myosin inhibitors, such as mavacamten, are known to reduce myocardial contractility by inhibiting the formation of excessive myosin-actin cross-bridges. Myosin inhibitors have been studied for the treatment of cardiac diseases, including obstructive hypertrophic cardiomyopathy (oHCM), non-obstructive hypertrophic cardiomyopathy (nHCM), and heart failure with preserved ejection fraction (HFpEF). Recently, the myosin inhibitor mavacamten has been shown to have clinical benefits in a Phase 3 clinical trial. Specifically, in the Phase 3 EXPLORER-HCM clinical trial, mavacamten treatment was effective in reducing LVOT gradient and improving symptoms, motor performance, and health status in a representative population of oHCM patients. (Olivotto et al., 2020, The Lancet, 396(10253), 759-769.) If approved, Mavaketide would be the first FDA-approved myosin inhibitor. However, due to the mechanism of action of myosin inhibitors, these drugs must be administered in a manner that mitigates the risk of excessive reduction in contractility, which can lead to systolic dysfunction and heart failure. Therefore, there is a need for methods of administering myosin inhibitors that maximize clinical benefit while minimizing the risk of adverse events, patient burden, cost, and complexity of administration. Summary of the invention

[0005] The present disclosure relates to methods for safely administering myosin inhibitors to patients. Various aspects and embodiments of such methods are described herein. In some embodiments, the methods include multiple treatment periods during which the myosin inhibitor is administered to the patient, or optionally during which administration is temporarily discontinued. In some cases, administration may be permanently discontinued. An evaluation can be performed at or near the end of a treatment period, and the results of the evaluation can be used to determine whether the dose administered during the treatment period should be increased, maintained, decreased, or discontinued during a subsequent treatment period. The evaluation and corresponding dosage adjustments provide for safe and effective administration of myosin inhibitors. Other aspects of the present disclosure include methods for concomitant administration of other drugs with myosin inhibitors, and methods for administering myosin inhibitors to avoid drug interactions. Other aspects of the present disclosure include methods for controlling the distribution of myosin inhibitors to mitigate risks. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 is a schematic diagram of the initial phase of a dosing regimen for administering myosin inhibitor.

[0007] Figure 2 is a schematic diagram of the maintenance phase of a dosing regimen for administering myosin inhibitor.

[0008] Figure 3 is a schematic representation of treatment interruption (temporary cessation) as part of a dosing regimen for administering myosin inhibitor.

[0009] Figure 4 is a schematic diagram of the initial phase of an exemplary dosing regimen for administering Mavaketel.

[0010] Figure 5 is a schematic diagram of the maintenance phase of an exemplary dosing regimen for administering mavaketide.

[0011] Figure 6 is a schematic representation of a treatment interruption (temporary stop) as part of an exemplary dosing regimen for administering mavacetel.

[0012] Figure 7 is a graph of the KCCQ-23 Clinical Summary scores: mean change from baseline over time.

[0013] Figure 8 is a graph of the KCCQ-23 Clinical Summary Score: Cumulative Distribution of Change from Baseline to Week 30.

[0014] Fig. 9 is a graph of the HCMSQ Shortness of Breath domain: mean change from baseline over time.

[0015] Fig.10is a graph of the HMCSQ Shortness of Breath Domain: Cumulative Distribution of Change from Baseline to Week 30.

[0016] Fig.11 is an exemplary schedule for echocardiographic assessment, PSF submission, and medication dispensing during the first 14 weeks after initiating myosin inhibitor therapy.

[0017] Fig.12 is an exemplary schedule for echocardiographic evaluation and medication dispensing during the first year after initiating myosin inhibitor therapy.

[0018] Fig.13A -D is a graph of the time course of the percentage of patients simulated according to Protocol #1 in Example 2 with (A) LVEF ≤ 50%, (B) VLVOT ≤ 30 mmHg, (C) mavaketal plasma concentration > 700 ng / mL, and (D) mavaketal plasma concentration > 1000 ng / mL, separated by patient phenotype.

[0019] Fig.14A -D is a graph of the time course of the percentage of patients simulated according to Protocol #2 in Example 2 with (A) LVEF ≤ 50%, (B) VLVOT ≤ 30 mmHg, (C) mavaketal plasma concentration > 700 ng / mL, and (D) mavaketal plasma concentration > 1000 ng / mL, separated by patient phenotype.

[0020] Fig.15A -D is a graph of the time course of the percentage of patients simulated according to Protocol #3 in Example 2 with (A) LVEF ≤ 50%, (B) VLVOT ≤ 30 mmHg, (C) mavaketal plasma concentration > 700 ng / mL, and (D) mavaketal plasma concentration > 1000 ng / mL, separated by patient phenotype.

[0021] Fig.16A and 16B Graphs of the simulated time course of the percentage of patients with LVEF <50% according to (A) Protocol #1 and (B) Protocol #2 according to Example 2, separated by PM and non-PM phenotypes.

[0022] Fig.17 Subgroup analyses of the Primary Composite Functional Endpoint of the clinical study described in Example 1 are shown.

[0023] Fig.18 The cumulative distribution of the change in LVOT peak gradient from baseline to Week 30 for the clinical study described in Example 1 is shown.

[0024] Fig.19The cumulative distribution of the change in pVO2 from baseline to week 30 for the clinical study described in Example 1 is shown.

[0025] Fig. 20A and 20B Steady-state mavacetide summary of (A) AUC and (B) Cmax geometric mean ratios from simulations of strong, moderate, and weak CYP2C19 and CYP3A4 inhibition.

[0026] Fig.21 is a schematic diagram of an exemplary system for authorizing the dispensing of a medication prescription.

[0027] Fig. 22 is a flow chart of an exemplary arrangement of operations of a method of authorizing the dispensing of a medication prescription.

[0028] Fig.23 is a schematic diagram of an exemplary computing device that can be used to implement the systems and methods described herein.

[0029] Fig.24 is a flow chart of another exemplary arrangement of operations of a method of authorizing dispensing of a medication prescription. DETAILED DESCRIPTION

[0030] definition

[0031] Although various embodiments and aspects of the present invention are shown and described herein, it is apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Without departing from the present invention, those skilled in the art will now expect numerous variations, changes and substitutions. It should be understood that in practicing the present invention, various alternatives of the embodiments of the present invention described herein may be adopted.

[0032] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

[0033] The following documents are incorporated by reference in their entirety:

[0034] ·The American Society of Echocardiography, Recommendations for Cardiac Chamber Quantification in Adults: A Quick Reference Guide from the ASEWorkflow and Lab Management Task Force, July 2018

[0035] ·Lang et al.,Recommendations for Cardiac Chamber Quantification byEchocardiography in Adults:An Update from the American Society ofEchocardiography and the European Association of Cardiovascular Imaging,Journal of the American Soci ety of Echocardiography,January 2015

[0036] ·Nagueh et al,Recommendations for the Evaluation of Left VentricularDiastolic Function by Echocardiography:An Update from the American Society ofEchocardiography and the European Association of Cardiovascular Imaging,Journal of the American Society of Echocardiography,2016;29:277-314

[0037] ·Caballero et al.,Echocardiographic reference ranges for normalcardiac Doppler data:results from the NORRE Study,European Heart Journal-Cardiovascular Imaging(2015)16,1031-1041

[0038] ·Jozine M.ter Maaten et al.,Connectin heart failure with preservedejection fraction and renal dysfunction;the role of endothelial dysfunctionand inflammation,European Journal of Heart Failure(2016)18,588-598

[0039] ·ATS / ACCP Statement on Cardiopulmonary Exercise Testing,AmericanThoracic Society / American College of Chest Physicians,November 1,2001

[0040] ·Zaid et al.Pre-and Post-Operative Diastolic Dysfunction in Patientswith Valvular Heart Disease,Journal of the American College of Cardiology,2013,62(21),1922-1930

[0041] ·Gupta et al.,Racial differences in circulating natriuretic peptidelevels;the atherosclerosis risk in communities study,Journal of the AmericanHeart Association,2015;4:e001831

[0042] ·Eugene Braunwald,Cardiomyopathies:An Overview,Circ Res.2017;121:711-721

[0043] ·Towbin and Jefferies, Cardiomyopathies Due to Left VentricularNoncompaction, Mitochondrial and Storage Diseases and Inborn Errors ofMetabolism, Circ Res. 2017; 121: 838-854

[0044] ·Cirino and Ho, Hypertrophic Cardiomyopathy Overview.2008In: Adam etal., eds., Seattle (WA): University of Washington, Seattle; 1993-2020.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. Devices and materials similar or equivalent to those described herein can be used in the practice of the present invention. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of the present disclosure.

[0046] As used herein, the terms "a" or "an" mean one or more.

[0047] The terms "include," "including," and "have" and their derivatives are used interchangeably herein as comprehensive, open-ended terms. For example, the use of "include," "comprising," or "having" means that any element included, having, or including is not the only element encompassed by the subject of the clause containing the verb.

[0048] As used herein, the term "about" means a range of values ​​including the specified value that one of ordinary skill in the art would reasonably consider to be similar to the specified value. In some embodiments, the term "about" means within the standard deviation of measurements generally accepted in the art. In some embodiments, "about" means a range extending to + / -10% of the specified value. In some embodiments, "about" means the specified value.

[0049] As used herein, "treatment" or "improvement" are used interchangeably herein. These terms refer to methods for obtaining beneficial or desired results, including but not limited to therapeutic benefits. Therapeutic benefit means eradication or improvement of the underlying condition being treated and / or eradication or improvement of one or more physiological symptoms associated with the underlying condition so that improvement is observed in the subject, although the subject may still suffer from the underlying condition. Treatment includes slowing the development of clinical symptoms of the disease by administering a composition; suppressing the disease, that is, alleviating the clinical symptoms of the disease; inhibiting the disease, that is, preventing the development of clinical symptoms by administering a composition after the initial onset of symptoms; and / or alleviating the disease, that is, causing clinical symptoms to subside by administering a composition after the initial onset of clinical symptoms. For example, certain methods described herein treat hypertrophic cardiomyopathy (HCM) by reducing or reducing the occurrence or progression of HCM, or treat HCM by alleviating the symptoms of HCM. Symptoms of HCM or test results indicative of HCM are known or ascertainable by one of ordinary skill in the art and may include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), syncope (especially during or just after exercise), rapid heartbeat, fluttering or racing sensations, atrial and ventricular arrhythmias, heart murmurs, left ventricular hypertrophy and non-dilation, myocardial thickening, left ventricular wall thickening, increased left ventricular outflow tract (LVOT) pressure gradient, and increased post-exercise or Valsalva LVOT gradient.

[0050] "Patient" or "subject" refers to a living organism suffering from or susceptible to a disease or condition that can be treated using the methods provided herein. The term does not necessarily mean that the subject has been diagnosed with a specific disease, but generally refers to an individual under medical supervision. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, cats, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient or subject is a human. In some embodiments, the patient suffers from obstructive HCM.

[0051] As used herein, "administration" of a disclosed compound includes delivering a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, e.g., as described herein. In some embodiments, administration is oral administration.

[0052] As used herein, "near the end" of a treatment period refers to a portion of the treatment period that is more than half of the entire treatment period and within about two weeks before the end of the treatment period. In some embodiments, near the end of the treatment period refers to more than half of the entire treatment period and within about 1 week before the end of the treatment period (e.g., within about 3 days, within about 1 day). In some embodiments, near the end of the treatment period is within + / - about two weeks before the end of the treatment period. In some embodiments, near the end of the treatment period is within + / - about one week before the end of the treatment period. In some embodiments, near the end of the treatment period refers to more than half of the entire treatment period and within the last two weeks of the treatment period. In some embodiments, near the end of the treatment period is the last week of the treatment period, such as the 4th week of a 4-week treatment period.

[0053] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0054] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and basic or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, phosphoric acid and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzoic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid.

[0055] Myosin inhibitors are being studied for the treatment of cardiac disorders, including obstructive hypertrophic cardiomyopathy (oHCM), non-obstructive hypertrophic cardiomyopathy (nHCM), and heart failure with preserved ejection fraction (HFpEF). While myosin inhibitors have been shown to provide clinical benefits, such as by reducing left ventricular outflow tract obstruction, they also carry the risk of excessively reducing left ventricular (LV) contractility due to their mechanism of action. Excessive reductions in LV contractility often result in systolic dysfunction, such as a left ventricular ejection fraction (LVEF) less than 50%, which can lead to heart failure and death. Myosin inhibitors can cause a decrease in LVEF when plasma concentrations of myosin inhibitors exceed the therapeutic range. Many pharmacokinetic factors can affect the plasma concentration of a drug, including the dose administered and the rate of metabolism. For example, mavaketide is primarily metabolized by the enzyme CYP2C19. Some individuals have mutations in the CYP2C19 enzyme that cause them to metabolize mavaketide at different rates, thus affecting plasma concentrations. Based on the mutation of CYP2C19, individuals can be grouped into poor metabolizers, moderate metabolizers, normal metabolizers, rapid metabolizers, and ultra-rapid metabolizers. For example, a CYP2C19 poor metabolizer who receives a daily dose of 5 mg of mavaketal for several weeks may reach a high mavaketal plasma concentration above the therapeutic range due to the slow metabolism rate of mavaketal, which poses a high risk of adverse events. As another example, a CYP2C19 ultra-rapid metabolizer who receives a daily dose of 5 mg of mavaketal for several weeks may have a low mavaketal plasma concentration below the therapeutic range due to the faster metabolism rate of mavaketal, which poses a reduced possibility of therapeutic benefit (e.g., reduced LVOT gradient). Therefore, the metabolism of mavaketal and other myosin inhibitors may vary in the expected patient population. A method of administering myosin inhibitors that maximizes the therapeutic benefit while minimizing the risk of adverse events, patient burden, cost, and complexity of administration is needed.

[0056] Disclosed herein are methods for treating cardiac disorders. Certain methods disclosed herein mitigate the risk of heart failure and systolic dysfunction during such treatments. In some embodiments, the risk is reduced, for example, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to other methods of administration. The methods may include specific methods of administration of myosin inhibitors, including dosage adjustments (reduction and / or increase), and specific assessment methods, such as echocardiography, left ventricular outflow tract obstruction assessment, and LVEF assessment, which can be used to guide the administration of myosin inhibitors. In some embodiments, the methods disclosed herein mitigate, manage, reduce, or reduce the risk of such adverse events.

[0057] In some embodiments, an aspect of the method includes determining the LVOT gradient or another measure of left ventricular outflow tract obstruction in one or more assessments after initiating treatment with a myosin inhibitor, and adjusting the dose as needed based on such assessments. The LVOT gradient is used as a measure of therapeutic benefit in treating oHCM and related cardiac conditions characterized by left ventricular outflow tract obstruction. When the LVOT gradient decreases rapidly after initiating myosin inhibitor therapy, this can infer that the patient's exposure to the myosin inhibitor is high. High levels of exposure to myosin inhibitors can create a risk of contractile dysfunction and heart failure. According to aspects of the present disclosure, the risk of contractile dysfunction and heart failure can be reduced by assessing the LVOT gradient (or another measure of left ventricular outflow tract obstruction) at or near the end of two or more separate treatment periods during the initial phase, and reducing the dose of myosin inhibitor administered based on low LVOT gradients in these assessments. As a specific example, the risk of systolic dysfunction and heart failure can be mitigated by assessing the Valsalva LVOT gradient at weeks 4 and 8 after the first administration of a myosin inhibitor (e.g., mavacetal) and reducing the dose of the myosin inhibitor (e.g., mavacetal) administered after weeks 4 and 8 when the Valsalva LVOT gradient is below a threshold (e.g., 20 mmHg). This criterion takes advantage of the exaggerated pharmacological effects early in treatment to prospectively reduce the dose in patients who are more likely to subsequently decrease in LVEF, before experiencing an episode of decreased LVEF.

[0058] Dose adjustments based on two or more LVOT assessments can also be combined with a method involving determining the LVEF in one or more assessments after (and optionally before) initiating treatment with a myosin inhibitor and modifying treatment based on the LVEF (e.g., by temporarily stopping it). Including an LVEF assessment may provide further risk mitigation for myosin inhibitor treatment. LVEF is a direct measure of systolic dysfunction, which can lead to heart failure. During the initiation of myosin inhibitor therapy, the use of LVEF and LVOT gradient provides two measurements to reduce the risk of systolic dysfunction and heart failure. Both the LVOT gradient and LVEF can be measured using non-invasive techniques, such as non-invasive imaging techniques (e.g., echocardiography, cardiac magnetic resonance imaging). When non-invasive techniques (e.g., imaging techniques, echocardiography) are used to determine the LVOT gradient and LVEF, the need for other procedures (including invasive procedures) can be eliminated. For example, the need to measure plasma concentrations (e.g., "trough" measurements) can be eliminated.

[0059] The use of one or more assessments also allows for administration to a broad patient population, for example by allowing the use of a "unified posology" regardless of the patient's genotype. Different patients will have different responses to myosin inhibitors and, therefore, some patients may be at greater risk for adverse events. For example, different exposure levels in different patients may place some patients at greater risk for adverse events. In particular, patients who are poor metabolizers of myosin inhibitors (e.g., due to a CYP2C19 (for mavacetel) or CYP2D6 (for aficamten) poor metabolizer phenotype) will experience higher and potentially dangerous exposure levels at a given dose, where the given dose may be an ideal starting dose for a large patient population, such as intermediate metabolizers, normal metabolizers, rapid metabolizers, and / or ultra-rapid metabolizers. In particular during the initial treatment ("start phase"), by providing the possibility of dose reduction and temporary suspension based on the relevant assessment results, all patients can start treatment at the same starting dose without the need for expensive or time-consuming genotyping assays. Patients who would be at reduced risk by reducing the administered dose or temporarily stopping administration can be identified promptly by assessments during the initiation phase (e.g., LVOT and / or LVEF) and given a dose reduction or temporary stop before exposure becomes too high. Patients at low risk for adverse events can be maintained on a higher dose during the initiation phase according to the same dosing regimen, rather than receiving a lower, potentially less effective dose.

[0060] In some embodiments, the methods include methods of mitigating, managing, reducing, or lowering the risk of adverse events of myosin inhibitor therapy.

[0061] In some embodiments, the methods include methods of mitigating, managing, reducing, or lowering the risk of adverse events due to myosin inhibitor therapy.

[0062] In some embodiments, the methods include methods of alleviating, managing, reducing, or lowering the risk of heart failure during myosin inhibitor therapy.

[0063] In some embodiments, the present methods relate to methods of alleviating, managing, reducing or lowering the risk of contractile dysfunction during myosin inhibitor therapy.

[0064] In some embodiments, the present methods relate to methods of alleviating, managing, reducing or lowering the risk of heart failure due to contractile dysfunction during myosin inhibitor therapy.

[0065] In some embodiments, the risk during the initiation phase is mitigated, managed, reduced or decreased by providing a dose reduction and / or treatment interruption (temporary cessation) during the initiation phase. The terms temporary cessation and treatment interruption are used interchangeably herein.

[0066] In some embodiments, the risks during the maintenance phase are mitigated, managed, reduced, or decreased by providing dosage adjustments and / or treatment interruptions (temporary stops) during the maintenance phase.

[0067] In some embodiments, the initial stage is about 2 weeks to about 36 weeks. In some embodiments, the initial stage is about 4 weeks to about 24 weeks. In some embodiments, the initial stage is about 4 weeks to about 16 weeks (e.g., 12 weeks). In some embodiments, the initial stage is about 8 weeks to about 24 weeks. In some embodiments, the initial stage is about 8 weeks to about 16 weeks. In some embodiments, the initial stage is about 4 weeks to about 12 weeks. In some embodiments, the initial stage is about 12 weeks. In some embodiments, the initial stage is about 8 weeks. In some embodiments, the initial stage is about 6 weeks. In some embodiments, the initial stage is about 4 weeks. In some embodiments, the initial stage is about 16 weeks.

[0068] In some embodiments, the methods include methods of treating a disease, or administering a myosin inhibitor while mitigating, managing, reducing, or lowering the risk of adverse events of myosin inhibitor therapy (e.g., heart failure, systolic dysfunction, or heart failure due to systolic dysfunction).

[0069] The method is applicable to treating patients with heart disease, heart disease, cardiovascular disease or symptoms thereof using myosin inhibitors. The method is applicable to a diverse patient population with different heart diseases and different characteristics, genotypes and phenotypes.

[0070] In some embodiments, the patient is a poor metabolizer of myosin inhibitors (e.g., mavaketal). In some embodiments, the patient is a normal metabolizer of myosin inhibitors (e.g., mavaketal). In other embodiments, the patient is a moderate, rapid, or ultra-rapid metabolizer of myosin inhibitors (e.g., mavaketal). The methods of the present disclosure can provide for administration of myosin inhibitors to patients regardless of the relative ability of the patient to metabolize myosin inhibitors (such as mavaketal). The dosing methods and assessments ensure that safe administration of myosin inhibitors (e.g., mavaketal) is provided in a diverse patient population, including poor metabolizers, moderate metabolizers, normal metabolizers, rapid metabolizers, and ultra-rapid metabolizers. The dosing methods also provide for initial administration without the need for genotyping assays, which can be both expensive and time-consuming, to determine the patient's metabolite genotype. This unified posology allows for timely assessment of patient response in the outpatient setting, reducing costs and reducing the complexity of administration. For example, physicians, pharmacists, and other interested parties do not need to be trained and certified on genotyping protocols (since genotyping is not required) or on multi-genotype specific dosing methods (which would further increase the complexity and risk of medication errors). The methods of the present disclosure may also provide for administration of myosin inhibitors to patients regardless of the patient's weight.

[0071] Myosin inhibitor (e.g., Mavaketal) poor metabolizers include individuals with CYP2C19 polymorphisms. In some embodiments, the poor metabolizer of myosin inhibitor (e.g., Mavaketal) is of Asian descent. In some cases, the poor metabolizer is of South Asian descent. In some embodiments, Asian descent includes but is not limited to Japanese populations, Chinese populations, Thai populations, Korean populations, Filipino populations, Indonesian populations, and Vietnamese populations. In some embodiments, the poor metabolizer of myosin inhibitor (e.g., Mavaketal) is not of Asian descent.

[0072] In some embodiments, the poor metabolizer of myosin inhibitor (e.g., mavaketal) has a CYP2C19 poor metabolizer genotype. In some embodiments, the poor metabolizer of myosin inhibitor (e.g., mavaketal) has a CYP2C19 *2 / *2, *2 / *3, or *3 / *3 genotype.

[0073] In some embodiments, the poor metabolizer of myosin inhibitor (eg, mavaketal) is of Asian descent. In some embodiments, the poor metabolizer of myosin inhibitor (eg, mavaketal) is of Japanese descent.

[0074] Poor metabolizers of myosin inhibitors (eg, Afroquita) may include individuals with CYP2D6 polymorphisms. In some embodiments, poor metabolizers of myosin inhibitors (eg, Afroquita) have a CYP2D6 poor metabolizer genotype.

[0075] In some embodiments, the patient treated by the methods described herein is diagnosed with and / or suffers from a cardiac disorder selected from the group consisting of hypertrophic cardiomyopathy (HCM), diastolic dysfunction, left ventricular hypertrophy, malignant left ventricular hypertrophy, angina, ischemia, restrictive cardiomyopathy (RCM), heart failure with preserved ejection fraction (HFpEF), and combinations thereof. In some cases, the patient treated by the methods described herein is diagnosed with and / or suffers from HCM and / or HFpEF.

[0076] In some embodiments, the patient treated by the methods described herein is diagnosed with and / or suffers from obstructive HCM (oHCM). In some such cases, the patient is diagnosed with and / or suffers from symptomatic NYHA II-III grade obstructive HCM. In some such cases, the patient is an adult. In other cases, the patient is a pediatric patient.

[0077] The NYHA functional class rates the severity of heart failure symptoms into one of four functional classes. The NYHA functional class is widely used in clinical practice and research because it provides a standard description of severity that can be used to assess response to treatment and guide management. The NYHA functional class based on symptom severity and physical activity is:

[0078] Class I: No limitation of physical activity. Ordinary physical activity does not cause excessive dyspnea, fatigue, or palpitations

[0079] Class II: Mild limitation of physical activity. Feels comfortable at rest, but ordinary physical activity causes excessive dyspnea, fatigue, or palpitations.

[0080] Class III: Physical activity is markedly limited. Feels comfortable at rest, but less than ordinary physical activity causes excessive dyspnea, fatigue, or palpitations.

[0081] Grade IV: Unable to perform any physical activity without discomfort. Symptoms may occur at rest. Discomfort increases with any physical activity.

[0082] In some embodiments, the patient is diagnosed with and / or suffers from HFpEF.

[0083] In some embodiments, the patient suffers from symptoms of cardiovascular disease, such as shortness of breath, dizziness, chest pain, syncope, or limitations in activities of daily living (eg, limitations in personal care, movement, or eating).

[0084] In some embodiments, the subject is diagnosed with and / or suffers from a condition (e.g., a cardiac condition) selected from valvular aortic stenosis, mixed LV systolic and diastolic dysfunction, idiopathic RV hypertrophy, chronic kidney disease, aortic insufficiency, tetralogy of Fallot, mitral stenosis, Noonan Syndrome, or acute coronary syndrome.

[0085] In some embodiments, the patient has normal systolic inotropy or excessive systolic inotropy, wherein the patient has a left ventricular ejection fraction > 50%.

[0086] In some embodiments, the patient suffers from any one or a combination of diastolic dysfunction, elevated left ventricular filling pressures, left ventricular hypertrophy, and / or left atrial enlargement (LAE).

[0087] Presence of diastolic dysfunction or key features of a range of diseases including but not limited to hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF), left ventricular hypertrophy (LVH) – including impairment of active relaxation and impairment of ventricular stiffness (diabetic HFpEF). Diastolic dysfunction may be diagnosed using one or more techniques and measurements including: catheterization, E / e', left atrial size, and BNP or NT-proBNP.

[0088] Individuals with HCM can be subdivided based on the presence or absence of left ventricular outflow tract obstruction (LVOT). The presence of LVOT obstruction, i.e., obstructive HCM (oHCM), is associated with more severe symptoms and a greater risk of heart failure and cardiovascular death. Limited data support medical therapy (beta blockers, calcium channel blockers, disopyramide) in this patient subset, and patients with persistent symptoms may be referred for invasive septal reduction therapy.

[0089] The ejection fraction is an indicator of normal or hypercontractile systolic function, ie, in patients with normal or hypercontractile systolic function, the ejection fraction is greater than about 52% or 50%.

[0090] LVH characterized by wall thickness can be diagnosed using one or more techniques and measurements including: echocardiography, cardiac MRI, non-invasive imaging techniques (eg, tissue Doppler imaging), and E / e'.

[0091] Patients in need of treatment for diastolic dysfunction include patients from a patient population characterized by oHCM, nHCM, LVH or HFpEF. Patients in need of treatment for diastolic dysfunction include patients exhibiting left ventricular stiffness as measured by echocardiography or left ventricular stiffness as measured by cardiac magnetic resonance.

[0092] In some embodiments, the patient in need thereof exhibits left ventricular stiffness as measured by echocardiography.

[0093] Further determinants for diastolic dysfunction using echocardiography are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the entire contents of which are incorporated herein by reference for all purposes.

[0094] In some embodiments, the patient in need thereof exhibits left ventricular stiffness as measured by cardiac magnetic resonance. Cardiac magnetic resonance is used to determine peak filling rate, peak filling time, and peak diastolic strain rate. Thus, in some embodiments, the patient has left ventricular stiffness as measured by cardiac magnetic resonance when at least one of the following characteristics is met: abnormal peak filling rate, peak filling time, or peak diastolic strain rate.

[0095] In some embodiments, the patient in need suffers from diastolic dysfunction, left ventricular hypertrophy, left ventricular outflow tract obstruction, increased left ventricular wall thickness (or mass index), increased interventricular septum (IVS) wall thickness, poor or decreased cardiac elasticity, poor or decreased left ventricular relaxation during diastole, abnormally high left atrial pressure, reduced E / e' ratio, reduced exercise capacity or endurance, reduced peak oxygen consumption (VO2), increased left ventricular diastolic pressure, or any combination thereof.

[0096] In some embodiments, the patient in need thereof suffers from hypertrophic cardiomyopathy (HCM) characterized by at least one biomarker selected from elevated levels of NT-pro B-type natriuretic peptide (NT-proBNP), elevated levels of cardiac troponin I. In another embodiment, the HCM patient in need thereof has a predisposition to develop HCM.

[0097] In some embodiments, the patient in need thereof suffers from chest pain, dyspnea, angina, syncope, or dizziness.

[0098] In some cases, when a myosin inhibitor is concomitantly administered with a compound that alters the activity of one or more cytochrome P450 (CYP) enzymes (e.g., CYP inducers, CYP inhibitors), the patient may be at risk for high exposure levels to the myosin inhibitor. For example, a patient receiving a myosin inhibitor that is primarily metabolized by CYP2C19 may experience high and unsafe exposure levels to the myosin inhibitor when concomitantly administered with a strong CYP2C19 inhibitor. In some cases, when a myosin inhibitor is concomitantly administered with a compound that alters the activity of one or more CYP enzymes (e.g., CYP inducers, CYP inhibitors), the patient may be at risk for less than effective exposure levels to the myosin inhibitor. For example, a patient receiving a myosin inhibitor that is primarily metabolized by CYP2D6 may experience less than effective exposure to the myosin inhibitor when concomitantly administered with a strong CYP2D6 inducer. In some cases, when a patient who is receiving concomitant administration of a myosin inhibitor and a compound that alters the activity of one or more CYP enzymes changes the dose of the compound (e.g., stops administration of the compound), the risk of excessive or low exposure to the myosin inhibitor may occur. The present disclosure encompasses methods of administering other drugs concomitantly with myosin inhibitors to mitigate, manage, reduce and / or decrease the above-mentioned risks.

[0099] In some embodiments, a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor is concomitantly administered to the patient during myosin inhibitor therapy (e.g., with mavaketide). For example, in some embodiments, the patient has not received a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, but then initiates administration of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor during myosin inhibitor therapy. In some embodiments, the weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor is selected from the group consisting of cimetidine, ciprofloxacin, diltiazem, felbamate, omeprazole at a dose of 20 mg once daily, isoniazid, fluconazole, and verapamil.

[0100] In some embodiments, a weak CYP2D6 inhibitor or inducer is concomitantly administered to the patient during myosin inhibitor therapy (eg, with Afroquine).

[0101] Mavaketide is metabolized primarily by the CYP2C19 enzyme and secondarily by the CYP3A4 enzyme. Therefore, concomitant administration of drugs that inhibit CYP2C19 and / or CYP3A4 may affect the metabolism of Mavaketide and the patient's structural exposure to Mavaketide. The inventors have determined that concomitant administration of Mavaketide and a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor can be safely achieved under certain conditions. Example 5 and Fig.17 The extent of exposure changes expected for concomitant administration of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor under the conditions described herein is demonstrated. Methods of concomitant administration are described herein below.

[0102] The methods described herein include administering a myosin inhibitor. In some embodiments, the myosin inhibitor is mavaketal or a pharmaceutically acceptable salt thereof. In some embodiments, the myosin inhibitor is mavaketal. Mavaketal has the following structure:

[0103]

[0104] Mavaketye is also known as MYK-461. Its chemical name is (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione or 3-(1-methylethyl)-6[[(1S)-1-phenylethyl]amino]-2,4(1H,3H)-pyrimidinedione.

[0105] Mavaketel can be obtained according to the preparation method described in US Patent No. 9,181,200, the entire contents of which are incorporated herein by reference for all purposes.

[0106] In some embodiments, the myosin inhibitor is a compound of formula (I):

[0107]

[0108] or a pharmaceutically acceptable salt thereof, wherein

[0109] R 1 C 1-8 Alkyl, C 3-8 Cycloalkyl or phenyl, where R 1 optionally substituted with one or two halo groups;

[0110] R 2 is phenyl optionally substituted by one or more halogen groups;

[0111] R 3 C 1-8 Alkyl or C 3-8 Cycloalkyl, where each R 3 Optionally substituted with halogen, hydroxyl or C 1-2 Alkoxy substitution;

[0112] R 4 is H; and

[0113] X is H.

[0114] In some embodiments, the myosin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0115]

[0116]

[0117] In some embodiments, the myosin inhibitor of formula (I) is MYK-581 or a pharmaceutically acceptable salt thereof having the following structure:

[0118]

[0119] The chemical name of MYK-581 is (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0120] Myosin inhibitors of formula (I), including compounds of group (I), mavacetate or MYK-581 or pharmaceutically acceptable salts thereof, can be obtained according to the preparation method described in U.S. Pat. No. 9,181,200, the entire contents of which are incorporated herein by reference and for all purposes.

[0121] In some embodiments, the myosin inhibitor is a compound of formula (II):

[0122]

[0123] or a pharmaceutically acceptable salt thereof, wherein

[0124] R 1 For fluorine, chlorine, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 2-4 Alkynyl, wherein at least one R 1 is fluorine; and R 2a and R 2b One of them is fluorine, R 2a and R 2b The other of is H, and n is 1 or 2.

[0125] In some embodiments, the myosin inhibitor of formula (II) or a pharmaceutically acceptable salt thereof is selected from Group (II) consisting of:

[0126]

[0127] Myosin inhibitors of formula (II), including compounds of group (II) or pharmaceutically acceptable salts thereof, can be obtained according to the preparation method described in international application number PCT / US2019 / 058297 filed on October 29, 2019, the entire contents of which are incorporated herein by reference and for all purposes.

[0128] In some embodiments, the myosin inhibitor is a compound of formula (III):

[0129]

[0130] or a pharmaceutically acceptable salt thereof, wherein

[0131] G1-CR 4 R 5 -or-O-;

[0132] G2 is a key or -CR 6 R 7 -;

[0133] G3-CR 8 -or-N-;

[0134] R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each is independently H, C1-C6 alkyl, halo or hydroxyl;

[0135] R 2 is H, C2-C6 alkyl, halo or hydroxyl;

[0136] Z is a bond, C1-C6 alkyl, -O-, -N(R 9 )-、-R X O-、-OR Y or -R Z S-;

[0137] R 9 is H, C1-C6 alkyl or cycloalkyl;

[0138] A is selected from the group consisting of substituted C2 alkynyl, unsubstituted C2 alkynyl, substituted phenyl, unsubstituted phenyl, and a 5-membered or 6-membered heteroaryl containing at least one ring N atom, wherein the 5-membered or 6-membered heteroaryl is unsubstituted or substituted by one or more R 10 Substituent substitution:

[0139] Each R 10are independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or -C(O)OR a ;

[0140] B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl of B is unsubstituted or replaced by one or more R 11 Substituent substitution;

[0141] Each R 11 independently selected from the group consisting of substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, unsubstituted C1-C6 alkyl, 12 Substituents: substituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, -OR b 、-C(O)R c 、-C(O)OR d , oxo and -NR e R f ;

[0142] Each R 12 are independently selected from halogen, -OR b 、-C(O)R g 、-C(O)OR h and -C(O)NR i R j The group composed of;

[0143] Each R a , R b , R c , R d , R e , R f , R g , R h , R i and R j are independently H or C1-C6 alkyl; and

[0144] R X , R Y and R Z Each is a C1-C6 alkyl group.

[0145] In some embodiments, the myosin inhibitor of formula (III) or a pharmaceutically acceptable salt thereof is selected from Group (III) consisting of:

[0146]

[0147]

[0148] Myosin inhibitors of formula (III), including compounds of group (III) or pharmaceutically acceptable salts thereof, can be obtained according to the preparation method described in International Publication No. WO 2019 / 144041 published on July 25, 2019, the entire contents of which are incorporated herein by reference and for all purposes.

[0149] In some embodiments, the myosin inhibitor is Afukate or a pharmaceutically acceptable salt thereof. Afukate has the following structure:

[0150]

[0151] In some embodiments, myosin inhibitors include compounds disclosed in PCT patent applications published as WO2020 / 005887, WO2020 / 005888, WO2020 / 047447, the entire contents of which are incorporated herein by reference and for all purposes.

[0152] The myosin inhibitors of the present invention are generally administered in the form of pharmaceutical compositions. Pharmaceutical compositions for administering compounds of formula (I), (II), (III) and / or compounds of groups (I), (II), (III) and / or mavacetia and / or MYK-581 or pharmaceutically acceptable salts thereof can be conveniently provided in unit dosage form and can be prepared by any method known in the art of pharmacy and drug delivery. Such methods include the step of combining the active ingredient with a carrier containing one or more auxiliary ingredients. Generally speaking, pharmaceutical compositions are prepared by uniformly and tightly combining the active ingredient with a liquid carrier or a fine solid carrier or both, and then molding the product into the desired formulation when necessary. In the pharmaceutical composition, the active agent is generally included in an amount sufficient to produce the desired effect on myocardial contractility (i.e., reduce the systolic contractility that is usually abnormal in HCM) and improve diastolic left ventricular relaxation. This improved relaxation can alleviate the symptoms of hypertrophic cardiomyopathy and other causes of diastolic dysfunction. It may also improve the effects of diastolic dysfunction leading to impaired coronary blood flow as an adjunct to angina and ischemic heart disease. It may also provide benefit in adverse left ventricular remodeling in HCM and other causes of left ventricular hypertrophy due to chronic volume or pressure overload, such as valvular heart disease or systemic hypertension.

[0153] Pharmaceutical compositions comprising a compound of formula (I), (II), (III) and / or a compound of group (I), (II), (III) and / or mavaketide and / or MYK-581 or a pharmaceutically acceptable salt thereof may be in a form suitable for oral use, for example as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gums, chewable tablets, effervescent powders and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may include one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants and preservatives to provide a pharmaceutically superior and palatable preparation. Tablets contain the active ingredient mixed with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binding agents such as PVP, cellulose, PEG, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated, or can be enteric or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thereby provide sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated to form osmotic therapeutic tablets for controlled release.

[0154] Preparations for oral use can also be prepared in the form of hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules, where the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil. In addition, emulsions can be prepared with water-immiscible ingredients such as oils and stabilized with surfactants such as mono- and di-glycerides, PEG esters, etc.

[0155] In some embodiments, the compound of formula (I), (II), (III) and / or the compound of group (I), (II), (III) and / or mavaketei and / or MYK-581 can be used in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts formed with inorganic bases, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids. In other embodiments, the compound of formula (I), (II), (III) and / or the compound of group (I), (II), (III) and / or mavaketei and / or MYK-581 can be used in the form of a free base.

[0156] The present disclosure includes a novel pharmaceutical dosage form of mavaketal or a pharmaceutically acceptable salt thereof. The dosage form described herein is suitable for oral administration to a patient. The dosage form can be any form suitable for oral administration, including but not limited to a capsule or a tablet. In some embodiments, the present disclosure provides a single unit dose capsule or tablet containing 1-25 mg (e.g., 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg or 25 mg) of mavaketal or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of mavaketal in a unit dose is about 2 mg to 5 mg, about 5 mg to 10 mg, about 2.5 mg or about 5 mg. In some embodiments, the single unit dosage form is a capsule. In some embodiments, the single unit dosage form is a tablet. In some embodiments, the pharmaceutical composition is a capsule filled with mavacetal, silicon dioxide, mannitol, hypromellose, croscarmellose sodium, and magnesium stearate. In some embodiments, the capsule shell contains gelatin and optionally contains titanium dioxide, black iron oxide, red iron oxide, and / or yellow iron oxide.

[0157] Methods of safely administering myosin inhibitors are described herein. Various aspects of these methods include: adjusting the dosage of myosin inhibitors administered to a patient over time based on an assessment of the patient over time, particularly an assessment of left ventricular outflow tract obstruction and / or left ventricular ejection fraction; methods including discontinuation of administration when certain conditions are met; methods of administering myosin inhibitors to a patient when the patient is receiving concomitant administration of certain other medications; methods of administering myosin inhibitors to avoid harmful drug interactions; and methods of controlling the distribution of myosin inhibitors to mitigate risk.

[0158] Myosin inhibitors can be administered by any suitable means known and described in the art. In some embodiments, myosin inhibitors are administered orally. In some embodiments, myosin inhibitors are administered in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition is an oral dosage form.

[0159] Examples of oral dosage forms include tablets, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. In some embodiments, the oral dosage form is a capsule. In other embodiments, the oral dosage form is a tablet.

[0160] According to the present disclosure, the dosage of the myosin inhibitor can be adjusted over time, ie, increasing the dosage, decreasing the dosage, maintaining the dosage, or interrupting the administration (temporarily stopping). In some embodiments, the dosage is adjusted stepwise. Figure 1 The initiation phase of the dosing regimen for myosin inhibitor is shown, during which the dose can be adjusted from one treatment period to the next. During the initiation phase, a starting dose is administered and then maintained or reduced. Figure 2 A maintenance phase is indicated during which the dose can be adjusted by interrupting treatment, maintaining the dose, or increasing the dose. Figure 3 The treatment interruption aspect of the dosing regimen is shown, where treatment can be interrupted and then restarted at a lower dose. For example, the daily dose of Mavaketel can be adjusted between some or all of the following daily doses: 0 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg. For example, a dose of 5 mg QD can be administered, then increased to 10 mg QD, reduced to 2.5 mg QD, or maintained at 5 mg QD. In some embodiments, step-dosing can include 1 mg as an additional dose. In some embodiments, step-dosing can include 7.5 mg as an additional dose. In the embodiments described herein, 7.5 mg can be included as an additional dose level; the embodiment describing an increase from 5 mg QD to 10 mg QD can alternatively use an increase from 5 mg QD to 7.5 mg QD, and according to the results of the relevant evaluation, it can be further increased from 7.5 mg QD to 10 mg QD and from 10 mg QD to 15 mg QD during subsequent treatment.

[0161] In some embodiments, the dosage is the total daily dosage administered once a day (QD). In other embodiments, the dosage is the total daily dosage administered twice a day (twice a day, BID).

[0162] The present disclosure relates to methods for safely administering myosin inhibitors to patients. Various aspects and embodiments of such methods are described herein. In some embodiments, the methods include multiple treatment periods during which a myosin inhibitor is administered to a patient, or optionally during which administration is temporarily stopped. An evaluation can be performed at or near the end of a treatment period, and the results of the evaluation can be used to determine whether the dose administered during the treatment period should be increased, maintained, decreased, or stopped during a subsequent treatment period. The evaluation and corresponding dosage adjustments provide for safe and effective administration of a myosin inhibitor.

[0163] The assessment is described in detail below, but may include an assessment of left ventricular outflow tract obstruction (e.g., Valsalva LVOT gradient) and / or an assessment of left ventricular ejection fraction (LVEF). The assessment may be performed during the treatment period, or at or near the end of the treatment period, such as during the last week of a multi-week treatment period. The dosage of the myosin inhibitor from one treatment period to the next can be adjusted based on the results of the assessment. In some embodiments, one treatment period (e.g., a first treatment period) is followed by the next treatment period (e.g., a second treatment period). For example, a first treatment period from days 1-28 may be followed by a second treatment period from days 29-56, wherein the myosin inhibitor is administered once a day on days 1-56. When there are multiple treatment periods, each treatment period may follow directly after the previous treatment period, whereby the myosin inhibitor is administered from one treatment period to the next without interruption. In other embodiments, administration of the myosin inhibitor may be interrupted between treatment periods.

[0164] In some embodiments, a starting dose of the myosin inhibitor is administered during the first treatment period. Figure 1 In some embodiments, the first treatment period is a portion of an initiation phase during which the dose of the myosin inhibitor is not increased and during which the dose of the myosin inhibitor may be decreased. Figure 1 As shown, the dosage may be reduced or maintained, but not increased, from the first treatment period to the second treatment period, and from the second treatment period to the third treatment period. Figure 4 As shown, the starting dose of the initial phase of mavaketal can be 5 mg QD mavaketal. In some embodiments, the duration of the first treatment period is about 1 week to about 12 weeks. In some embodiments, the duration of the first treatment period is about 2 weeks to about 12 weeks. In some embodiments, the duration of the first treatment period is about 2 weeks to about 8 weeks. In some embodiments, the duration of the first treatment period is about 2 weeks to about 6 weeks. In some embodiments, the duration of the first treatment period is about 3 weeks to about 4 weeks. In some embodiments, the duration of the first treatment period is about 4 weeks. In some embodiments, the duration of the first treatment period is about 20 days to about 35 days. In some embodiments, the duration of the first treatment period is about 22 days to about 28 days.

[0165] In some embodiments, a second dose of the myosin inhibitor is administered during a second treatment period (ie, after the first treatment period). Figure 1As shown, the second dose is determined based on the first evaluation and is administered during the second treatment period. An evaluation is also performed at or near the end of the second treatment period to determine the dose to be administered during the third treatment period. In some embodiments, the second treatment period is part of a starting phase during which the dose of the myosin inhibitor is not increased and during which the dose of the myosin inhibitor may be decreased. In some embodiments, the second dose is less than or equal to the starting dose. In some embodiments, the second dose is less than the starting dose. In some embodiments, the second dose is the same as the starting dose. For example, Figure 4 As shown, the second dose of mavaketal can be 2.5 mg QD mavaketal. As another example, Figure 4 As shown, the second dose of mavaketal may be 5 mg QD mavaketal. In some embodiments, the duration of the second treatment period is about 1 week to about 12 weeks. In some embodiments, the duration of the second treatment period is about 2 weeks to about 12 weeks. In some embodiments, the duration of the second treatment period is about 2 weeks to about 8 weeks. In some embodiments, the duration of the second treatment period is about 2 weeks to about 6 weeks. In some embodiments, the duration of the second treatment period is about 3 weeks to about 4 weeks. In some embodiments, the duration of the second treatment period is about 4 weeks. In some embodiments, the duration of the second treatment period is about 20 days to about 35 days. In some embodiments, the duration of the second treatment period is about 22 days to about 28 days.

[0166] In some embodiments, a third dose of myosin inhibitor is administered during a third treatment period (ie, after the second treatment period). Figure 1 As shown, the third dose is determined based on the second evaluation results and is administered during the third treatment period. The evaluation is also performed at or near the end of the third treatment period to determine the dose administered during the fourth treatment period. In some embodiments, the third treatment period is part of the starting phase, during which the dose of the myosin inhibitor is not increased and during which the dose of the myosin inhibitor may be reduced. In some embodiments, the third dose is less than or equal to the starting dose. In some embodiments, the third dose is less than the starting dose. In some embodiments, the third dose is the same as the starting dose. In some embodiments, the third dose is less than or equal to the second dose. In some embodiments, the third dose is less than the second dose. In some embodiments, the third dose is the same as the second dose. In some embodiments, the third dose is 2.5 mg QD mavakettai. For example, the third dose of mavakettai may be 5 mg QD mavakettai. As another example, the third dose may be 1 mg QD mavakettai. In some cases, the third dose of mavakettai is 0 mg QD mavakettai. Figure 4Examples of different doses that can be administered as a third dose during the third treatment period are shown. Administering 0 mg of myosin inhibitor (e.g., mavaketal) during the treatment period refers to a period of time when the patient is stopped from taking the myosin inhibitor (e.g., mavaketal). In some embodiments, the third dose is 0 mg QD or 1 mg QD mavaketal, and the patient is a poor metabolizer. In some embodiments, the third dose is 0 mg QD or 1 mg QD mavaketal, and the patient receives concomitant administration of a CYP2C19 inhibitor or inducer (e.g., a weak CYP2C19 inhibitor or inducer) or a CYP3A4 inhibitor or inducer (e.g., a weak or moderate CYP3A4 inhibitor or inducer). In some embodiments, the myosin inhibitor is not administered during the third treatment period. In some embodiments, the duration of the third treatment period is about 1 week to about 12 weeks. In some embodiments, the duration of the third treatment period is about 2 weeks to about 12 weeks. In some embodiments, the duration of the third treatment period is about 2 weeks to about 8 weeks. In some embodiments, the duration of the third treatment period is about 2 weeks to about 6 weeks. In some embodiments, the duration of the third treatment period is about 3 weeks to about 4 weeks. In some embodiments, the duration of the third treatment period is about 4 weeks. In some embodiments, the duration of the third treatment period is about 20 days to about 35 days. In some embodiments, the duration of the third treatment period is about 22 days to about 28 days.

[0167] In some embodiments, a fourth dose of myosin inhibitor is administered during a fourth treatment period (ie, after the third treatment period). Figure 1 As shown, the fourth treatment period can be regarded as the beginning of the maintenance phase after the initiation phase. Figure 2 As shown, the maintenance phase adopts the criteria of increasing the dose, maintaining the same dose, or interrupting treatment (temporary stop) according to the evaluation results (e.g., the evaluation results of LVEF and LVOT gradient). In some embodiments, the fourth treatment period is part of the maintenance phase, during which the dose of myosin inhibitor can be increased. In some embodiments, the fourth dose is greater than the third dose. In some embodiments, when the fourth dose is greater than the third dose, this represents an increase in the first dose during the treatment period. Therefore, the fourth dose can be the first increased dose and the fourth treatment period can be the first treatment period during which the increased dose is administered. In some embodiments, the fourth dose is the same as the third dose. In some embodiments, the fourth dose is 0 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg QD mavaketide. Figure 5The example of the standard for determining the fourth dosage is shown. In some embodiments, the duration of the fourth treatment period is about 2 weeks to about 26 weeks (or 6 months). In some embodiments, the duration of the fourth treatment period is about 4 weeks to about 24 weeks. In some embodiments, the duration of the fourth treatment period is about 4 weeks to about 16 weeks. In some embodiments, the duration of the fourth treatment period is about 8 weeks to about 24 weeks. In some embodiments, the duration of the fourth treatment period is about 8 weeks to about 16 weeks. In some embodiments, the duration of the fourth treatment period is about 12 weeks (or about 3 months). In some embodiments, the duration of the fourth treatment period is about 80 days to about 100 days. In some embodiments, the duration of the fourth treatment period is about 84 days to about 90 days.

[0168] In some embodiments, a fifth dose of myosin inhibitor is administered during a fifth treatment period (i.e., after the fourth treatment period). In some embodiments, the fifth treatment period is part of a maintenance phase during which the dose of myosin inhibitor may be increased. The fifth dose may be based on Figure 2 In some embodiments, the fifth dose is greater than the fourth dose. In some embodiments, the fifth dose is the same as the fourth dose. In some embodiments, the fifth dose is 2.5 mg, 5 mg, 10 mg, or 15 mg QD mavaketide. Figure 5 The example of the standard for determining the fifth dosage during the maintenance phase is shown. In some embodiments, the duration of the fifth treatment period is about 2 weeks to about 26 weeks (or 6 months). In some embodiments, the duration of the fifth treatment period is about 4 weeks to about 24 weeks. In some embodiments, the duration of the fifth treatment period is about 4 weeks to about 16 weeks. In some embodiments, the duration of the fifth treatment period is about 8 weeks to about 24 weeks. In some embodiments, the duration of the fifth treatment period is about 8 weeks to about 16 weeks. In some embodiments, the duration of the fifth treatment period is about 12 weeks (or about 3 months). In some embodiments, the duration of the fifth treatment period is about 80 days to about 100 days. In some embodiments, the duration of the fifth treatment period is about 84 days to about 90 days.

[0169] In some embodiments, the method further comprises additional treatment periods after the fifth treatment period (i.e., a sixth treatment period, a seventh treatment period, etc.). These additional treatment periods may be part of a maintenance phase during which the dose of the myosin inhibitor may be increased. In some embodiments, the dose administered during the additional treatment period is based on Figure 2 In some embodiments, the additional treatment period is equal in duration to the fourth and / or fifth treatment period.

[0170] In some embodiments, administration of the myosin inhibitor is temporarily stopped, for example, during the first treatment period, the second treatment period, the third treatment period, the fourth treatment period, or the fifth treatment period. Figure 3 As shown, a temporary stop (treatment interruption) may be indicated based on the evaluation results (e.g., based on LVEF). In some embodiments, the duration of the temporary stop is about 1 week to about 12 weeks, for example, the duration is about 2-8 weeks, about 3-4 weeks, or about 4 weeks. In some embodiments, a patient's LVEF is below a safety threshold (e.g., as described herein) to trigger a temporary stop. In some embodiments, a patient's LVOT gradient is below a threshold (e.g., as described herein) to trigger a temporary stop. For example, Figure 6 As shown, the threshold value may be 50%. Thus, during a treatment with a myosin inhibitor for multiple treatment sessions, administration of the myosin inhibitor may be temporarily stopped when an assessment during a treatment session shows that the LVEF and / or LVOT gradient is below the threshold value; and the temporary stop may be implemented by not administering the myosin inhibitor during the treatment session immediately following the treatment session in which the assessment was performed.

[0171] In some embodiments, administration of the myosin inhibitor is permanently discontinued. For example, the permanent discontinuation can be implemented after the second treatment period, the third treatment period, the fourth treatment period, or the fifth treatment period. In some embodiments, administration is permanently discontinued after treatment was temporarily discontinued during a previous treatment period. In some embodiments, administration is permanently discontinued after treatment was temporarily discontinued during a previous treatment period and resumed after the temporary discontinuation. Figure 3 As shown in FIG. 1 , if the LVEF is less than the safety threshold for the second time when the lowest dose (twice) is received, the administration may be permanently discontinued. Permanent discontinuation can be determined based on an assessment (e.g., an LVEF assessment, the result of which is that the LVEF is less than the safety threshold). Specifically, in some embodiments, when administration was previously discontinued due to LVEF being less than 50%, administration is permanently discontinued when the LVEF is less than 50% in an assessment performed after administration is resumed. For example, Figure 6 As shown, when administration was previously discontinued during administration of 2.5 mg QD mavaketal due to LVEF less than 50%, administration is permanently discontinued when LVEF is less than 50% in an assessment performed after resumption of administration of 2.5 mg QD mavaketal. In some embodiments, treatment may be resumed if discontinuation is due to temporary factors despite meeting the criteria for permanent discontinuation.

[0172] Certain methods described herein include an initiation phase. In some embodiments, the initiation phase includes a first treatment period and a second treatment period. In some embodiments, the initiation phase includes a first treatment period, a second treatment period, and a third treatment period. In some embodiments, the initiation phase includes a first treatment period, a second treatment period, a third treatment period, and a fourth treatment period. In some embodiments, the initiation phase includes a first treatment period, a second treatment period, and a third treatment period, as well as a portion of a fourth treatment period. In some embodiments, during the initiation phase, the dose of the myosin inhibitor is not increased. In some embodiments, during the initiation phase, the myosin inhibitor does not reach steady-state pharmacokinetics, or does not reach steady-state pharmacokinetics until the end of or near the end of the initiation phase in certain patients (e.g., poor metabolizers). In some embodiments, the myosin inhibitor is mavaketide, and steady-state pharmacokinetics is reached after about 10 weeks of daily administration in patients. In some embodiments, the myosin inhibitor is mavaketide, and steady-state pharmacokinetics is reached after about 12 weeks of daily administration in certain patients (e.g., poor metabolizers).

[0173] Certain methods described herein include a maintenance phase. In some embodiments, the maintenance phase includes a fourth treatment period. In some embodiments, the maintenance phase includes a fifth treatment period. In some embodiments, the maintenance phase includes an additional treatment period after the fourth treatment period and the fifth treatment period. In some embodiments, the myosin inhibitor is in a steady state during the maintenance phase, or reaches a steady state at or near the beginning of the maintenance phase.

[0174] In some embodiments, myosin inhibitors are concomitantly administered with weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors. In some embodiments, myosin inhibitors are concomitantly administered with weak CYP2D6 inhibitors (e.g., Afroquita). When such agents are concomitantly administered, additional steps may be required to provide safe administration of the myosin inhibitor. As described above, Afroquita is primarily metabolized by CYP2C19 and secondarily by CYP3A4. Therefore, agents that inhibit these enzymes, especially in patients with a poor metabolizer genotype, can result in reduced metabolism of Afroquita and potentially high exposure. In some embodiments, concomitant administration of a weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor is initiated while the patient is receiving myosin inhibitor therapy. In some embodiments, concomitant administration is initiated while the patient is receiving a stable dose of a myosin inhibitor, for example during or after the third treatment period, the fourth treatment period, or the fifth treatment period. In some embodiments, the weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor is selected from the group consisting of cimetidine, ciprofloxacin, diltiazem, felbamate, omeprazole at a dose of 20 mg once daily, isoniazid, fluconazole, and verapamil.

[0175] Disclosed herein are certain methods for safely administering a myosin inhibitor concomitantly with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. In some embodiments, a first daily dose of a myosin inhibitor is administered during a first treatment period prior to initiating concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor; and a second daily dose of a myosin inhibitor less than the first daily dose is administered during a second treatment period, wherein the patient receives concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor during the second treatment period. In some embodiments, a method for treating HCM in a patient who is being administered a first daily dose of mavaketide, wherein the patient requires concurrent treatment with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor in addition to mavaketide, the method comprising administering a second daily dose of mavaketide to the patient in addition to administering a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, wherein the second daily dose is less than the first daily dose. In some embodiments, the myosin inhibitor is mavaketal, the first daily dose is 5 mg, 10 mg, or 15 mg QD mavaketal, and the second daily dose is 2.5 mg, 5 mg, or 10 mg QD mavaketal.

[0176] When the patient is receiving stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, mavaketide can be started at a starting dose of 5 mg. Disclosed herein is a method of administering mavaketide to a patient who is receiving administration of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, the method comprising: (a) determining that the patient is receiving stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor; and (b) administering mavaketide to the patient starting at a daily dose of 5 mg per day.

[0177] Also disclosed herein is a method of administering a myosin inhibitor (e.g., mavacetel) to a patient who initiates or increases the dose of concomitant therapy with a negative inotropic drug while receiving myosin inhibitor therapy, the method comprising: (a) administering a therapeutically effective amount of the myosin inhibitor during a first treatment period; (b) continuing to administer the myosin inhibitor during a second treatment period, wherein during the second treatment period the patient initiates or increases the dose of concomitant therapy with a negative inotropic drug; and (c) providing echocardiographic monitoring of LVEF during the second treatment period. In some embodiments, echocardiographic monitoring of LVEF is provided until a stable dose and clinical response is achieved. In some embodiments, close medical supervision is provided during the second treatment period.

[0178] Example 4 describes a study using drug-drug interaction simulations that suggested that mavacetib is contraindicated with both strong and moderate inducers of CYP2C19 and CYP3A4.

[0179] Also disclosed herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the subject a therapeutically effective amount of mavaketide, wherein the patient is not receiving concomitant administration of a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer.

[0180] Also disclosed herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, wherein the patient is being treated with a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer, the method comprising: ceasing administration of the strong or moderate CYP2C19 inducer or the strong or moderate CYP3A4 inducer to the patient; and administering a therapeutically effective amount of mavaketide to the subject, thereby avoiding the use of mavaketide in combination with the strong or moderate CYP2C19 inducer or the strong or moderate CYP3A4 inducer.

[0181] In some embodiments, the methods of the present disclosure comprise performing one or more assessments of the patient. Figure 1-3 An exemplary schematic diagram of an evaluation and corresponding dosage adjustment is shown. One or more evaluations can be used to determine the dosage of myosin inhibitor to be administered to a patient. For example, an evaluation during a treatment period or at the end of a treatment period can be used to determine the dosage of myosin inhibitor to be administered during the next treatment period, such as increasing, maintaining, decreasing, or stopping the dosage during the next treatment period. For example, Figure 1 An assessment of the LVOT gradient performed or obtained at the end of a treatment period and used to guide the dose administered in a subsequent treatment period is shown. In some embodiments, the assessment is performed at or near the end of a treatment period, such as during the last week of a multi-week treatment period.

[0182] In some embodiments, a patient is assessed for left ventricular outflow tract obstruction. In some embodiments, a patient's LVOT gradient is assessed. In some embodiments, the LVOT pressure gradient is measured at rest. In some embodiments, the individual's pressure gradient across the LVOT is measured during or immediately after performing a Valsalva maneuver ("Valsalva LVOT gradient"). In some embodiments, the individual's LVOT pressure gradient is measured after exercise. In some embodiments, a patient's LVEF is assessed.

[0183] In some embodiments, non-invasive techniques are used for assessment. In some embodiments, the non-invasive technique is an imaging technique (e.g., a cardiac imaging technique). In some embodiments, the non-invasive technique is echocardiography. In some embodiments, the non-invasive technique is two-dimensional echocardiography. In some embodiments, two-dimensional echocardiography is used to determine LVEF. In some embodiments, the non-invasive technique is Doppler echocardiography. In some embodiments, Doppler echocardiography is used to determine the LVOT gradient. In some embodiments, the non-invasive technique is transthoracic echocardiography. In alternative embodiments, the non-invasive technique is transesophageal echocardiography. Cardiac imaging techniques can be used as a non-invasive technique. For example, cardiac magnetic resonance imaging can be used. Cardiac magnetic resonance imaging can be used to measure LVEF. An alternative technique for measuring LVEF and / or LVOT gradient is cardiac catheterization.

[0184] In some embodiments, at the end of each of two or more treatment periods (e.g., at the start-up phase), the patient's left ventricular outflow tract obstruction (e.g., LVOT gradient) is assessed, e.g., Figure 1 As shown. Based on these assessments, the dose administered to the patient can be reduced to reduce the risk of systolic dysfunction and heart failure. There are several benefits to multiple (i.e., two or more) assessments of left ventricular outflow tract obstruction and corresponding dose adjustments. First, by providing more than one assessment that can lead to dose reduction in the initial stage, patients who will benefit from dose reduction can be identified in the second (or subsequent) assessment, and these patients were not identified in the first assessment (for example, because the dangerous exposure level was not found in the first assessment), thereby reducing the risk of adverse events in these patients. At the same time, a higher starting dose can be used because there are multiple opportunities to reduce the dose based on the assessment of left ventricular outflow tract obstruction, so that it is safe to start treatment with a higher dose for the entire patient population. This benefits them with a lower risk of adverse events by allowing a large portion of the patient population to receive a larger therapeutic dose at the start of treatment. In addition, by providing more than one assessment, it is not necessary to perform an overly conservative dose reduction after the first assessment, because the second (or subsequent) assessment can identify additional patients who will benefit from dose reduction. This enables more patients to maintain the starting dose throughout the initial stage, rather than reducing the dose and then increasing it later. In addition, by providing more than one assessment during the initiation phase that can lead to a dose reduction, patients for whom a single dose reduction still results in excessive drug exposure can have their dose reduced even lower, or the drug temporarily discontinued. Example 2 describes an exemplary dosing regimen for mavacetal and provides data showing the benefit of providing two LVOT gradient assessments during the initiation phase and allowing for corresponding dose reductions.

[0185] In some embodiments, both the LVOT gradient and LVEF of a patient are assessed during multiple treatment sessions. Using an LVEF assessment in addition to an LVOT gradient assessment can provide further risk mitigation. In some embodiments, the dose administered during a treatment session is determined based on an assessment of the LVOT gradient and LVEF during a previous treatment session (e.g., during the last week of a previous treatment session). In some embodiments, and during some treatment sessions, the LVOT gradient and LVEF results are used in parallel to determine a dose adjustment, i.e., the dose for the next treatment session. For example, Figure 2 As shown, if the LVEF is below a safety threshold, then administration is stopped during the next treatment period regardless of the LVOT gradient result; and if the LVOT gradient is below a threshold, then the dose is reduced (or increased) during the next treatment period, regardless of the LVEF result, unless the LVEF result requires stopping administration. In some embodiments, the LVOT gradient and LVEF results are used in combination to determine the dose for the next treatment period. For example, again referring to Figure 2 If the LVEF is above a threshold and the LVOT gradient is above a threshold, the dose is increased; but if the LVEF is below a threshold or the LVOT gradient is below a threshold, the dose is maintained. In some embodiments, when the LVEF is below a safety threshold (e.g., 50%), administration is stopped (temporarily or permanently) regardless of the LVOT gradient measured in the same assessment.

[0186] In some embodiments, the method does not include assessing the pharmacokinetics of the myosin inhibitor in the patient during the treatment period, for example, the method does not include assessing the plasma concentration of the myosin inhibitor (eg, mavacetal) during the treatment period.

[0187] In some embodiments, a pre-treatment assessment (or "baseline" assessment) is performed. In some embodiments, a pre-treatment assessment is performed up to about 12 weeks before the start of administration of the myosin inhibitor (e.g., up to about 8 weeks, up to about 4 weeks, about 8-12 weeks, about 6-10 weeks, about 4-8 weeks, about 2-6 weeks, or about 1-4 weeks before the start of administration). The pre-treatment assessment may include, for example, an assessment of the LVEF performed by echocardiography. The pre-treatment assessment results can be obtained from the pre-treatment assessment. Some methods may further include determining whether the pre-treatment assessment results are above or below a threshold. Some methods may further include determining whether the patient's LVEF is below a pre-treatment LVEF threshold. In some embodiments, the pre-treatment LVEF threshold is a percentage value between 40% and 65%, such as about 60%, about 55%, about 52%, or about 50%. In some embodiments, the pre-treatment LVEF threshold is about 55%. In some embodiments, the pre-treatment LVEF threshold is about 50%. In some embodiments, when the LVEF from the pre-treatment assessment is below the pre-treatment LVEF threshold, the myosin inhibitor is not administered to the patient, and when the LVEF from the pre-treatment assessment is above the pre-treatment LVEF threshold, the myosin inhibitor is administered at a starting dose for a first treatment period.

[0188] In some embodiments, a first assessment is performed or obtained. Figure 1 As a non-limiting example, the first assessment may be performed at or near the end of the first treatment period. In some embodiments, the first assessment is performed during the last week of the first treatment period (e.g., as described herein). For example, the duration of the first treatment period may be 28 days, and the first assessment result may be performed between the 22nd and 28th day of the first treatment period. In some embodiments, the assessment is performed during the last week of the treatment period. In some embodiments, the first assessment includes assessing left ventricular outflow tract obstruction by non-invasive techniques to obtain a first assessment result. The method may further include determining whether the first assessment result is above or below a threshold. As Figure 1 As shown, the first assessment may include assessing the LVOT gradient. In some embodiments, the first assessment includes assessing the LVOT gradient using a Valsalva maneuver to obtain a first Valsalva LVOT gradient. In some embodiments, the non-invasive technique is echocardiography. In some embodiments, the non-invasive technique is an imaging technique. The method may further include determining whether the first Valsalva LVOT gradient is less than a Valsalva LVOT gradient threshold. The Valsalva LVOT gradient threshold may be a value between 20 mmHg and 30 mmHg, such as 20 mmHg, 25 mmHg, or 30 mmHg. In some embodiments, the Valsalva LVOT gradient threshold is approximately 20 mmHg.

[0189] In some embodiments, the first assessment includes (e.g., further includes) assessing LVEF to obtain a first LVEF. The method may also include determining whether the first LVEF is above or below a LVEF threshold. The LVEF threshold can be a percentage value between 40% and 65%, for example, about 60%, about 55%, about 52%, or about 50%. In some embodiments, the LVEF threshold is about 55%. In some embodiments, the LVEF threshold is about 50%. Echocardiography can be used to assess the first LVEF. Imaging techniques can be used to assess the first LVEF.

[0190] In some embodiments, a second assessment is performed or obtained. Figure 1 The second assessment may be performed at or near the end of the second treatment period. In some embodiments, the second assessment is performed during the last week of the second treatment period (e.g., as described herein). In some embodiments, the second assessment includes assessing left ventricular outflow tract obstruction by non-invasive techniques to obtain a second assessment result. The method may further include determining whether the second assessment result is above or below a threshold. Figure 1 As shown, the second assessment may include assessing the LVOT gradient. In some embodiments, the second assessment includes assessing the LVOT gradient using a Valsalva maneuver to obtain a second Valsalva LVOT gradient. In some embodiments, the non-invasive technique is echocardiography. In some embodiments, the non-invasive technique is an imaging technique. The method may further include determining whether the second Valsalva LVOT gradient is less than a Valsalva LVOT gradient threshold. The Valsalva LVOT gradient threshold may be a value between 20 mmHg and 30 mmHg, such as 20 mmHg, 25 mmHg, or 30 mmHg. In some embodiments, the Valsalva LVOT gradient threshold is approximately 20 mmHg.

[0191] In some embodiments, the second assessment includes (e.g., further includes) assessing LVEF to obtain a second LVEF. The method may also include determining whether the second LVEF is above or below a LVEF threshold. The LVEF threshold can be a percentage value between 40% and 65%, for example, about 60%, about 55%, about 52%, or about 50%. In some embodiments, the LVEF threshold is about 55%. In some embodiments, the LVEF threshold is about 50%. Echocardiography can be used to assess the second LVEF. Imaging techniques can be used to assess the second LVEF.

[0192] Additional assessments similar to the first and second assessments may also be performed or obtained, such as during an initiation phase.

[0193] In some embodiments, a third assessment is performed or obtained. In some embodiments, the third assessment is performed at or near the end of the third treatment period (e.g., as described herein). For example, the third assessment may be performed during the last week of the third treatment period. In some embodiments, the third assessment may be considered as a transition point from the start-up phase to the maintenance phase. In some embodiments, the third assessment includes assessing left ventricular outflow tract obstruction by non-invasive techniques to obtain a third assessment result. The method may further include determining whether the third assessment result is above or below a threshold. In some embodiments, the third assessment includes assessing the LVOT gradient using the Valsalva maneuver to obtain a third Valsalva LVOT gradient. In some embodiments, the non-invasive technique is echocardiography. In some embodiments, the non-invasive technique is imaging technology. The method may further include determining whether the third Valsalva LVOT gradient is greater than the Valsalva LVOT gradient threshold. The Valsalva LVOT gradient threshold may be a value between 20 mmHg and 35 mmHg, such as 20 mmHg, 25 mmHg, 30 mmHg, or 35 mmHg.

[0194] In some embodiments, the third assessment includes assessing LVEF to obtain a third LVEF. The method may also include determining whether the third LVEF is above or below a LVEF threshold. The LVEF threshold can be a percentage value between 40% and 65%, for example, about 60%, about 55%, about 52%, or about 50%. In some embodiments, the LVEF threshold is about 55%. In some embodiments, the LVEF threshold is about 50%. Echocardiography can be used to assess the third LVEF. Imaging techniques can be used to assess the third LVEF.

[0195] Additional assessments similar to the third assessment may also be performed or obtained, for example, at or near the end of a fourth or fifth treatment period (eg, as described herein).

[0196] Each of the assessments described herein may further include assessing the patient for other symptoms, for example, other oHCM symptoms such as new or worsening dyspnea, chest pain, fatigue, palpitations, leg edema, or elevated N-terminal (NT) prohormone b-type natriuretic peptide (NTproBNP).

[0197] The dose of myosin inhibitor can be adjusted based on one or more assessment results (e.g., LVOT gradient and / or LVEF), as described herein. In some embodiments, when the first assessment result is below the threshold LVOT gradient, the starting dose is reduced, for example, to a second dose. Figure 1 , when the LVOT gradient is less than a threshold, the dose is reduced, and when the LVOT gradient is greater than or equal to the threshold, the dose is maintained. Figure 4As an example, when the first Valsalva LVOT gradient is less than 20 mmHg, the starting dose of 5 mg QD mavaketal is reduced to 2.5 mg QD. A second dose (e.g., 2.5 mg QD mavaketal) is then administered until another assessment is performed. Figure 1 In some embodiments, when the first evaluation result is greater than or equal to the threshold LVOT gradient, the starting dose is maintained, for example, the second dose is the same as the starting dose. Figure 4 As an example, when the first Valsalva LVOT gradient is greater than or equal to 20 mmHg, then administration of 5 mg QD Mavaketel is continued until another assessment is performed.

[0198] In some embodiments, when the second evaluation result is below the threshold LVOT gradient, the second dose is reduced, for example to a third dose. Figure 1 , when the LVOT gradient is less than the threshold, the dose is reduced or stopped, and when the LVOT gradient is greater than or equal to the threshold, the dose is maintained. Figure 4 As an example, at week 8, when the Valsalva LVOT gradient is less than 20 mmHg, the dose is reduced, and when the Valsalva LVOT gradient is greater than or equal to 20 mmHg, the dose is maintained. In some embodiments, when the second Valsalva LVOT gradient is less than 20 mmHg, the dose of 2.5 mg QD mavaketal is reduced to 1 mg QD or to 0 mg (or the dose of 5 mg QD mavaketal is reduced to 2.5 mg QD). A third dose (e.g., 0 or 1 mg QD mavaketal, or 2.5 mg QD) is then administered until another assessment is performed. In some embodiments, when the second assessment result is greater than or equal to the threshold LVOT gradient, the second dose is maintained, for example, the third dose is the same as the second dose. In some embodiments, when the second Valsalva LVOT gradient is greater than or equal to 20 mmHg, the second dose (e.g., 2.5 mg or 5 mg QD mavaketal) is continued to be administered (as the third dose) until another assessment is performed.

[0199] In some embodiments, when the third assessment result is above the threshold LVOT gradient, the third dose is increased, for example to a fourth dose. Figure 1 Dosing regimens are shown that progressed into the maintenance phase. Figure 2 A maintenance phase criterion is shown whereby the LVOT gradient, for example, combined with LVEF assessment, guides dose adjustments. If the LVEF is greater than the LVEF threshold, the dose can be increased when the LVOT gradient is greater than or equal to the threshold. Figure 5As an example, when the third Valsalva LVOT gradient is greater than or equal to 30 mmHg, the third dose (e.g., 0 mg or 1 mg QD mavaketal) is increased to 2.5 mg (or the 2.5 mg dose is increased to 5 mg QD, or the 5 mg dose is increased to 10 mg QD or 7.5 mg QD). Then the fourth dose (e.g., 2.5 mg QD mavaketal, or 5 mg, 7.5 mg, or 10 mg QD) is administered until another assessment is performed. In some embodiments, when the third assessment result is below the threshold LVOT gradient, the third dose is maintained, for example, the fourth dose is the same as the third dose. In some embodiments, when the third Valsalva LVOT gradient is less than 30 mmHg, the third dose (e.g., 0 mg, 1 mg, 2.5 mg, or 5 mg QD mavaketal) is continued to be administered (as the fourth dose) until another assessment is performed.

[0200] In some embodiments, the third assessment includes assessing LVEF. In some embodiments, the LVEF is compared to a LVEF threshold (e.g., about 50%, about 52%, about 55%, or about 60%). In some embodiments, when the LVEF of the third assessment is less than the LVEF threshold (e.g., 55%), the dose is not increased even if the Valsalva LVOT gradient is greater than or equal to the threshold Valsalva LVOT gradient (e.g., the Valsalva LVOT gradient is greater than or equal to 30 mmHg). Figure 2 It shows that both LVEF and LVOT gradient must be greater than or equal to their respective thresholds before dose can be increased. Figure 5 As an example, at week 12, when the Valsalva LVOT gradient is greater than or equal to 30 mmHg and the LVEF is greater than or equal to 55%, the dose is increased; otherwise, the dose is maintained (assuming that the criteria for temporary discontinuation (dose interruption) are not met).

[0201] In some embodiments, when the fourth evaluation result is greater than or equal to the threshold LVOT gradient, the fourth dose is increased, for example, to a fifth dose. The criteria for the evaluation and dose adjustment may also be as follows: Figure 2Maintenance phase criteria as shown. In some embodiments, when the fourth Valsalva LVOT gradient is greater than or equal to 30 mmHg, the dose of myosin inhibitor is increased (e.g., from 0 mg or 1 mg to 2.5 mg QD mavaketal, from 2.5 mg to 5 mg QD mavaketal, from 5 mg to 10 mg QD mavaketal, or from 10 mg to 15 mg QD mavaketal, or from 5 mg to 7.5 mg QD or from 7.5 mg to 10 mg QD). The fifth dose is then administered until another assessment is performed. In some embodiments, when the fourth assessment is below the threshold LVOT gradient, the fourth dose is maintained, for example, the fifth dose is the same as the fourth dose. In some embodiments, when the fourth Valsalva LVOT gradient is less than 30 mmHg, the fourth dose (e.g., 0 mg, 1 mg, 2.5 mg, 5 mg, 7.5 mg, or 10 mg QD mavaketal) (as the fifth dose) is continued until another assessment is performed.

[0202] In some embodiments, the fourth assessment includes assessing LVEF. In some embodiments, for example, Figure 2 As shown, the LVEF is compared to a LVEF threshold (e.g., about 50%, about 52%, about 55%, or about 60%). In some embodiments, when the LVEF at the fourth assessment is less than the LVEF threshold (e.g., 55%), the dose is not increased even if the Valsalva LVOT gradient is greater than or equal to the threshold LVOT gradient (e.g., the Valsalva LVOT gradient is greater than or equal to 30 mmHg).

[0203] In some embodiments, such as during the maintenance phase, when the dose of the myosin inhibitor is increased, an additional assessment is performed. In some embodiments, the additional assessment is an LVEF assessment. For example, when the dose of the myosin inhibitor is increased after the third assessment at the end of the third treatment period (e.g., at the beginning of the maintenance phase), an additional assessment of LVEF is performed during the fourth treatment period. In some embodiments, an additional assessment of LVEF is performed about 4 weeks after the dose increase.

[0204] refer to Figure 3In some embodiments, when the assessment result includes LVEF and the LVEF is less than a safety threshold (e.g., less than 50%), the administration of the myosin inhibitor is interrupted (temporarily stopped). In some embodiments, when the assessment result includes LVEF and the LVEF is greater than or equal to a safety threshold (e.g., less than 50%), the myosin inhibitor is continued to be administered (e.g., at the same or different dose). The LVEF assessment result may be determined at or near the end of the first, second, third, fourth, or fifth treatment period. In some embodiments, the assessment of LVEF occurs at or near the end of a treatment period (e.g., a first treatment period), and the temporary stop includes not administering the myosin inhibitor during the next treatment period (e.g., a second treatment period).

[0205] Still refer to Figure 3 In some embodiments, after the temporary suspension, the administration of the myosin inhibitor is resumed after a subsequent LVEF assessment shows that the LVEF is greater than or equal to a safety threshold (e.g., 50%). In some embodiments, administration is resumed at a dose lower than the dose received immediately before the temporary suspension. In some embodiments, for example, when it is determined that the suspension is due to a temporary factor (e.g., atrial fibrillation or other uncontrolled tachycardia or severe infection), administration is resumed at the same dose as the dose received immediately before the temporary suspension. In some embodiments, the dose is resumed at the minimum dose, which is the minimum dose of the myosin inhibitor approved by the government regulatory agency for administration to the patient. In some embodiments, the government regulatory agency is an agency in the United States, the European Union, Switzerland, Japan, China, South Korea, Canada, Mexico, Australia, New Zealand, Brazil, Russia, Ukraine, Georgia, Vietnam, Singapore, Malaysia, the Philippines, India, Indonesia, Israel, South Africa, Colombia, Costa Rica, the Dominican Republic, Ecuador, Guatemala, El Salvador, Honduras, Egypt, Syria, Algeria, Kenya, Morocco, or Nigeria.

[0206] In some embodiments, when the assessment results include LVEF, and the LVEF is less than a safety threshold (eg, less than 50%), and administration of the myosin inhibitor was previously temporarily discontinued and then resumed, administration of the myosin inhibitor is permanently discontinued.

[0207] Reference again Figure 3 In some embodiments, when the assessment results include LVEF, and the LVEF is less than a safety threshold (e.g., less than 50%), and the administration of the myosin inhibitor was previously temporarily stopped due to LVEF less than 50% during a previous assessment and then previously resumed, the administration of the myosin inhibitor is permanently stopped.

[0208] refer to Figure 6As an example, in some embodiments, when the assessment results include LVEF and the LVEF is less than 50% and the patient is receiving 2.5 mg QD mavaketela, and administration of the myosin inhibitor was previously temporarily discontinued during the previous assessment due to LVEF less than 50% while the patient was receiving 2.5 mg QD mavaketela, and then was previously resumed at a dose of 2.5 mg QD mavaketela, administration of the myosin inhibitor is permanently discontinued.

[0209] The assessment can also be performed in a method involving concomitant administration of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. In some embodiments, the assessment includes assessing the patient's LVEF during the treatment period of initiating concomitant administration, and temporarily stopping the administration of the myosin inhibitor if the LVEF is below a safety threshold. In some embodiments, the safety threshold is 50%. In some embodiments, the assessment includes assessing the patient's LVEF and LVOT gradient after cessation of administration, and resuming administration when the LVOT gradient is above a threshold LVOT gradient and the LVEF is greater than or equal to a threshold LVEF. In some embodiments, the threshold LVOT gradient is 30 mmHg, and the threshold LVEF is 55%. In some embodiments, assessing the patient's LVEF includes assessing the patient's LVEF about four weeks after starting concomitant therapy or during the fourth week after starting concomitant therapy.

[0210] In some embodiments, the method includes setting, following, and / or enforcing protocols and restrictions related to the distribution of myosin inhibitors or pharmaceutical compositions thereof to pharmacies and patients. These protocols and restrictions may be part of a risk evaluation and mitigation strategy (REMS) program. In some embodiments, the purpose of the REMS program is to mitigate the risk of heart failure due to systolic dysfunction. In some embodiments, the REMS will teach prescribers, patients, and pharmacies about the risk of heart failure due to systolic dysfunction, certify prescribers and pharmacies in the REMS, enroll patients in the REMS, and limit the distribution of Mavaketal only by certified pharmacies to enrolled patients who have prescriptions written by certified prescribers and patients who have a current patient status form (PSF) indicating that an echocardiogram has been performed at the required frequency (e.g., an echocardiogram assessment for Valsalva LVOT gradient and LVEF as described herein). In some embodiments, Mavaketal is distributed to certified pharmacies in accordance with REMS requirements.

[0211] In some embodiments, the present risk mitigation method comprises submitting a patient status form (PSF) in accordance with an assessment as described herein. For example, after the LVOT gradient and / or LVEF are assessed by echocardiography, the PSF is completed and submitted to a risk management administrator. In some embodiments, the PSF is completed and submitted within 1 day, 2 days, or 3 days (e.g., within 2 days) of the echocardiography assessment. In some embodiments, the PSF contains a physician's statement on the results of the assessment, such as whether the LVOT gradient is above or below a threshold and / or whether the LVEF is above or below a threshold.

[0212] In some embodiments, the present risk mitigation methods include a dispensing limit, wherein a certain number of days of medication is requested, supplied, and / or received. In some embodiments, the dispensing limit for a myosin inhibitor (or a pharmaceutical composition thereof) is a 28 to 90 day supply, or a 28 to 56 day supply, or a 30-40 day supply, such as a 35 day supply. For example, in some embodiments, the method includes requesting a myosin inhibitor (or a pharmaceutical composition thereof) be dispensed to a pharmacy, hospital, physician, or patient, wherein the amount requested is equal to the dispensing limit (e.g., a 35 day supply).

[0213] Figure 8 A schedule for echocardiographic evaluations, PSF submissions, and dispensing during the first 14 weeks after initiating myosin inhibitor therapy is shown. The implementation rules are as follows. Each "Week X echo" should occur within that week (e.g., a Week 4 echo should occur between Days 22 and 28). Prescribers will be taught to schedule their patients' Week 4, Week 8, and Week 12 echoes at the start of treatment to support scheduling approximately 4 weeks apart. Prescribers will be taught to submit their PSF within 2 days of the echo. A deadline will be set in the REMS Administrator portal to submit the PSF within 3 days of the echo deadline (e.g., the deadline for Week 4 is Day 31). Dispensing will be suspended until the PSF is received. Once the PSF is received, pharmacy authorization and dispensing will occur (e.g., for Week 4, this can occur any time between Days 22 and 31). The pharmacy must confirm the PSF submission and authorize dispensing by the PSF submission deadline (e.g., for Week 4, the pharmacy must authorize dispensing by Day 31). Under this rule, patients will receive new fills from the date the echo is made until 4 days after the PSF submission deadline (based on the standard time range from pharmacy authorization to patient receipt of medication, which is 0 to 4 days, with an average of 2 days). The 35-day fill limit ensures that access to medications is not interrupted while prescribers interpret the first echo, submit the PSF, and the pharmacy authorizes the fill and ships the medication to the patient. Fig. 9The schedule for echocardiographic evaluations and medication dispensing during the first year after initiating myosin inhibitor therapy is shown. In year 2 and beyond, when patients are on a stable dose (i.e., no dose change within 12 weeks), the medication dispensing will be increased to a 90-day period; if the patient needs a dose change, the medication dispensing will be for a 35-day period. Once the patient is back on a stable dose, the medication dispensing will be restored to a 90-day period.

[0214] In some embodiments, disclosed herein is a method for controlling the dispensing of a myosin inhibitor, the method comprising: certifying a healthcare provider and a pharmacy in a risk mitigation program; enrolling a patient in the risk mitigation program; receiving a patient status form containing information about one or more echocardiographic evaluations performed on the patient during treatment with the myosin inhibitor; receiving confirmation that a drug-drug interaction screen has been performed; processing the patient status form; and authorizing the dispensing of the myosin inhibitor to the pharmacy, wherein the authorization is subject to a dispensing restriction.

[0215] In some embodiments, the information in the patient status form about one or more echocardiographic assessments includes (i) information about the Valsalva LVOT gradient of the patient during treatment with the myosin inhibitor and (ii) information about the LVEF of the patient during treatment with the myosin inhibitor. In some embodiments, the information about the Valsalva LVOT gradient is information about whether the Valsalva LVOT gradient has been determined. In some embodiments, the information about the Valsalva LVOT gradient is information about whether the Valsalva LVOT gradient is above or below one or more thresholds. In some embodiments, the information about the LVEF is information about whether the LVEF has been determined. In some embodiments, the information about the LVEF is information about whether the LVEF is above or below one or more thresholds. In some embodiments, the method further includes providing information about drug interactions. In some embodiments, the dispensing restriction is to provide a 28 to 90 day supply, or a 28 to 56 day supply, or a 30 to 40 day supply, such as a 35 day supply of the myosin inhibitor to the pharmacy. In some embodiments, the patient status form must be submitted within a specified time window, for example, at or near the end of the treatment period described herein. In some embodiments, the method includes verifying that the echocardiogram was performed within a specified time window and / or that a patient status form containing echocardiogram information was submitted within a specified time window. In some embodiments, if the patient status form is not received within the specified time window and / or if the echocardiogram was not performed within the specified time window, then dispensing of the medication is not authorized.

[0216] In some embodiments, the method further includes suspending the dispensing of the medication until a patient status form is received. In some embodiments, the method further includes suspending the dispensing of the medication until a complete patient status form is received, and continuing to suspend the dispensing of the medication when an incomplete patient status form is received. In some embodiments, the method further includes suspending the dispensing of the medication when the patient status form indicates that the patient's LVEF is less than 50%. In some embodiments, information about one or more echocardiographic assessments in the patient status form is received via a web-based portal. In some embodiments, receiving confirmation that a drug interaction screen has been performed includes receiving confirmation from a pharmacy and / or a healthcare provider. In some embodiments, receiving confirmation that a drug interaction screen has been performed includes receiving confirmation from a pharmacy and a healthcare provider. In some embodiments, receiving confirmation that a drug interaction screen has been performed further includes receiving confirmation from a healthcare provider that there is no drug interaction. In some embodiments, receiving confirmation that a drug interaction screen has been performed further includes receiving confirmation from a pharmacy that there is no drug interaction.

[0217] In some embodiments, the patient status table is received via a data storage facility. The data storage facility may include a database of patient records, each patient record having a dispensing authorization field for entering a first prescription for Malvacetta. The REMS system may also include a central controller having one or more processors coupled to a communications network, the central controller coupled to the data storage facility to read data from and write data to the data storage facility via the network. The REMS system may also include a drug storage facility in which Malvacetta is stored. The central controller of the system may be programmed to monitor drug inventory in the drug storage facility, and further programmed to control the dispensing of Malvacetta from the drug storage facility.

[0218] The central controller can control the transmission and reception of data to and from the data storage facility over the network. The central controller can be programmed to output, over the network, a first prescription for a first dispensing authorization of Malvacetta to a specific patient who has previously been evaluated (e.g., as described herein). In some embodiments, the output of the dispensing authorization depends on the results of the evaluation, e.g., echocardiogram, LVOT gradient, LVEF. The central controller can also be programmed to output the time period during which the patient is authorized to use Malvacetta and schedule a follow-up evaluation of the patient, requiring receipt of the patient's follow-up test results before authorizing the dispensing of additional Malvacetta for the patient. The central controller can be programmed to take actions based on the follow-up test results, including authorizing additional prescriptions, changing prescriptions, and outputting recommendations to stop prescriptions.

[0219] refer to Fig.21In some embodiments, the exemplary medication dispensing authorization system 100 includes a remote system 140 that communicates with one or more user devices 10 via, for example, one or more networks. The remote system 140 can be a single computer, multiple computers, or a distributed system (e.g., a cloud environment) with scalable / elastic resources 142, including computing resources 144 (e.g., data processing hardware) and / or storage resources 146 (e.g., memory hardware). A data storage 148 (i.e., a remote storage device) can be overlaid on the storage resources 146 to allow one or more clients (e.g., user devices 10) or computing resources 144 to scalably use the storage resources 146. Additionally or alternatively, the data storage 148 is independent of the remote system 140, and the remote system 140 communicates with the data storage via, for example, a network.

[0220] The remote system 140 executes a dispensing authorization controller 150. The dispensing authorization controller 150 obtains or receives a healthcare professional (HCP) assessment record 20 associated with the patient 14. The HCP assessment record 20 includes the procedure results 22 or assessments described herein. In some embodiments, the procedure results 22 include echocardiographic results. For example, the echocardiographic results include left ventricular ejection fraction (LVEF), left ventricular outflow tract (LVOT) gradient, etc. derived from the echocardiographic procedure. In some instances, the HCP assessment record 20 includes risk events (e.g., one or more clinical heart failure events) and / or the risk of potential drug interactions. The dispensing authorization controller 150 can receive the HCP assessment record 20 from the healthcare provider 12 via the user device 10 (e.g., at a doctor's office, hospital, or other healthcare provider facility).

[0221] The dispensing authorization controller 150 also obtains a pharmacy assessment record 30 associated with the patient 14. The pharmacy assessment record 30 includes the medical condition 32 of the patient 14 (e.g., heart disease, allergies, etc.). Additionally or alternatively, the pharmacy assessment record 30 includes concomitant medications and supplements and / or potential drug-drug interactions. The dispensing authorization controller 150 may obtain or receive the pharmacy assessment record 30 from the pharmacy 34 or other entity on behalf of the pharmacy 34. The HCP assessment record 20 and / or the pharmacy assessment record 30 may be stored in the data storage 148 along with any number of other records 20, 30 for any number of patients 14. The healthcare provider 12, the pharmacy 34, and any other entity may automatically upload the record 20, 30 to the data storage 148 when it is available. Alternatively, the dispensing authorization controller 150 may request the record 20, 30 (e.g., periodically or on demand) and store the received record 20, 30 in the data storage 148.

[0222] The dispensing authorization controller 150 can use the HCP assessment record 20 to determine whether the patient 14 is authorized to receive a prescription authorization 152 that authorizes the patient 14 to use the prescription medication 36. In some instances, the prescription medication includes a myosin inhibitor, such as mavacetal. In some embodiments, the dispensing authorization controller 150 determines whether the patient 14 is authorized to receive the prescription medication 36 in response to a prescription request (e.g., from the patient 14, the healthcare provider 12, and / or the pharmacy 34). In some instances, the healthcare provider (e.g., at the pharmacy 34, such as a pharmacist) determines whether the prescription authorization 152 is available (e.g., by querying the dispensing authorization controller 150 and / or the data storage 148). When the healthcare provider determines that the patient 14 has the prescription authorization 152, the healthcare provider can provide the pharmacy assessment record 30 to the dispensing authorization controller 150. That is, in some instances, the healthcare provider (e.g., the pharmacist) provides the pharmacy assessment record 30 to the dispensing authorization controller 150 and / or the data storage 148 in response to receiving or verifying the prescription authorization 152.

[0223] When the patient 14 is authorized to receive a prescription authorization 152 (e.g., the program result 22 indicates that the patient 14 is a satisfactory candidate for the prescription medication 36), the dispensing authorization controller 150 uses the pharmacy evaluation record 30 to determine whether the pharmacy 34 is authorized to dispense the prescription medication 36 to the patient 14. For example, the dispensing authorization controller 150 determines whether the pharmacy evaluation record 30 includes satisfactory pharmacy information (e.g., regarding the patient's medical condition 32), concomitant medications and supplements, and / or potential drug-drug interactions (e.g., between different medications received by the patient 14).

[0224] When the pharmacy 34 is authorized to dispense a prescription medication to the patient 14 , the dispensing authorization controller 150 generates a dispensing authorization 154 and transmits the prescription authorization 152 and / or the dispensing authorization 154 to the pharmacy 34 .

[0225] The pharmacy 34 may dispense or distribute the prescription medication 36 to the patient 14 as authorized by the dispensing authorization 154. For example, the dispensing authorization 154 includes the amount of the prescription medication 36 that the patient 14 is authorized to receive and / or the time period during which the patient 14 is authorized to receive the prescription medication 36 (e.g., a dosage plan that specifies when and / or how often the prescription medication 36 is to be taken). The dispensing authorization controller 150 may use the HCP assessment record 20 and / or the pharmacy assessment record 30 to determine that the dispensing authorization 154 indicates a non-standard supply of the prescription medication 36 (e.g., an amount and / or frequency that is greater than or less than a standard supply or dosage).

[0226] Pharmacy 34 may require an updated or new dispensing authorization 154 before adjusting the amount, time period, or any other parameter for dispensing prescription medication 36 to patient 14. In some embodiments, dispensing authorization controller 150 determines (e.g., after a period of time has passed) whether updated procedure results 22 associated with patient 14 are available.

[0227] For example, the dispensing authorization controller 150 determines whether new or updated procedure results 22 are available from the healthcare provider 12 or the data storage 148 (e.g., the patient 14 underwent a second procedure to obtain updated procedure results 22). When updated procedure results 22 are not available, the dispensing authorization controller 150 may refuse to update the dispensing authorization 154, thereby prohibiting the pharmacy from adjusting the amount or time period of the prescribed medication 36 (e.g., denying any refills). When updated procedure results 22 are available, the dispensing authorization controller 150 may update the dispensing authorization 154 with the updated procedure results. For example, the updated dispensing authorization adjusts the amount of the prescribed medication 36 that the patient 14 is authorized to receive and / or adjusts the time period (e.g., dosage schedule) during which the patient 14 is authorized to receive the prescribed medication 36.

[0228] In some embodiments, the dispensing authorization controller 150 generates a report when the patient 14 is not authorized to receive the prescription medication 36 and / or the pharmacy 34 is not authorized to dispense the prescription medication 36 to the patient 14. For example, when the HCP assessment record 20 and / or the pharmacy assessment record 30 includes unsatisfactory reporting information (e.g., regarding experiencing clinical heart failure), the dispensing authorization controller 150 automatically generates a report that includes or references the unsatisfactory information and transmits the report to one or more regulatory agencies.

[0229] Fig. 22is a flow chart of an exemplary arrangement of operations for a computer-implemented method 2200 that, when executed by the data processing hardware 144, causes the data processing hardware 144 to operate. The method 2200 includes, at operation 2202, obtaining an HCP assessment record 20 associated with the patient 14. The HCP assessment record includes a procedure result 22. At operation 2204, the method 2200 includes using the HCP assessment record 20 to determine whether the patient 14 is authorized to receive a prescription authorization 152 authorizing the use of a prescription medication 36. When the patient 14 is authorized to receive the prescription medication 36, the method 2200 includes, at operation 2206, obtaining a pharmacy assessment record 30 associated with the patient 14. The pharmacy assessment record 30 includes a medical condition 32 of the patient 14. At operation 2208, the method 2200 includes using the pharmacy assessment record 30 to determine whether the pharmacy 34 is authorized to dispense the prescription medication 36 to the patient 14. When the pharmacy 34 is authorized to dispense the prescription medication 36 to the patient 14 , the method 2200 also includes generating a dispensing authorization 154 at operation 2210 and transmitting the dispensing authorization 154 to the pharmacy 34 at operation 2212 .

[0230] Fig.24 is a flow diagram of an alternative exemplary arrangement of operations for a computer-implemented method 200 that, when executed by the data processing hardware 144, causes the data processing hardware 144 to perform operations. The method 200, at operation 202, includes obtaining an HCP assessment record 20 associated with the patient 14. The HCP assessment record includes a procedure result 22. At operation 204, the method 200 includes obtaining a pharmacy assessment record 30 associated with the patient 14. The pharmacy assessment record 30 includes a medical condition 32 of the patient 14. At operation 206, the method 200 includes using the HCP assessment record 20 to determine whether the patient 14 is authorized to receive a prescription authorization 152 authorizing the use of a prescription medication 36. When the patient 14 is authorized to receive the prescription medication 36, the method 200 includes: at operation 208, using the pharmacy assessment record 30 to determine whether the pharmacy 34 is authorized to dispense the prescription medication 36 to the patient 14, and when the pharmacy 34 is authorized to dispense the prescription medication 36 to the patient 14, at operation 210, generating a dispensing authorization 154, and at operation 212, transmitting the dispensing authorization 154 to the pharmacy 34.

[0231] Fig.23 23 is a schematic diagram of an exemplary computing device 2300 that can be used to implement the systems and methods described in this document. Computing device 2300 is intended to represent various forms of digital computers, such as laptops, desktops, workstations, personal digital assistants, servers, blade servers, mainframes, and other appropriate computers. The components shown here, their connections and relationships, and their functions are intended to be exemplary only and are not intended to limit the implementation of the inventions described and / or claimed in this document.

[0232] The computing device 2300 includes a processor 2310, a memory 2320, a storage device 2330, a high-speed interface / controller 2340 connected to the memory 2320 and a high-speed expansion port 2350, and a low-speed interface / controller 2360 connected to a low-speed bus 2370 and the storage device 2330. Each of the components 2310, 2320, 2330, 2340, 2350, and 2360 is interconnected using various buses and can be mounted on a common motherboard or in other appropriate ways. The processor 2310 can process instructions for execution within the computing device 2300, including instructions stored in the memory 2320 or on the storage device 2330, to display graphical information of a graphical user interface (GUI) on an external input / output device (such as a display 2380 connected to the high-speed interface 2340). In other embodiments, multiple processors and / or multiple buses, as well as multiple memories and multiple types of memories, can be used as appropriate. Furthermore, multiple computing devices 2300 may be connected, with each device providing portions of the necessary operations (eg, in the form of a server bank, a group of blade servers, or a multi-processor system).

[0233] Memory 2320 stores information within computing device 2300 non-temporarily. Memory 2320 may be a computer-readable medium, a volatile memory unit, or a non-volatile memory unit. Non-temporary memory 2320 may be a physical device for temporarily or permanently storing programs (e.g., instruction sequences) or data (e.g., program state information) for use by computing device 2300. Examples of non-volatile memory include, but are not limited to, flash memory and read-only memory (ROM) / programmable read-only memory (PROM) / erasable programmable read-only memory (EPROM) / electronically erasable programmable read-only memory (EEPROM) (e.g., typically used for firmware, such as boot programs). Examples of volatile memory include, but are not limited to, random access memory (RAM), dynamic random access memory (DRAM), static random access memory (SRAM), phase change memory (PCM), and disk or tape.

[0234] Storage device 2330 can provide mass storage for computing device 2300. In some embodiments, storage device 2330 is a computer readable medium. In various embodiments, storage device 2330 can be a floppy disk device, a hard disk device, an optical disk device, or a tape device, a flash memory or other similar solid-state memory device, or a device array, including a device in a storage area network or other configuration. In other embodiments, a computer program product is tangibly embodied in an information carrier. The computer program product includes instructions that, when executed, perform one or more methods, such as those described above. The information carrier is a computer or machine readable medium, such as a memory on memory 2320, storage device 2330, or processor 2310.

[0235] The high-speed controller 2340 manages bandwidth-intensive operations of the computing device 2300, while the low-speed controller 2360 manages less bandwidth-intensive operations. Such allocation of responsibilities is exemplary only. In some embodiments, the high-speed controller 2340 is connected to the memory 2320, the display 2380 (e.g., through a graphics processor or accelerator) and to the high-speed expansion port 2350 that can accept various expansion cards (not shown). In some embodiments, the low-speed controller 2360 is connected to the storage device 2330 and the low-speed expansion port 2390. The low-speed expansion port 2390, which can include various communication ports (e.g., USB, Bluetooth, Ethernet, wireless Ethernet), can be connected to one or more input / output devices, such as keyboards, pointing devices, scanners, or network devices such as switches or routers, for example, through a network adapter.

[0236] The computing device 2300 can be implemented in many different forms, as shown in the figure. For example, it can be implemented as a standard server 2300a, or multiple implementations in a group of such servers 2300a, implemented as a laptop 2300b, or implemented as part of a rack-mounted server system 2300c.

[0237] Various implementations of the systems and techniques described herein can be realized in digital electronic and / or optical circuits, integrated circuits, specially designed ASICs (application specific integrated circuits), computer hardware, firmware, software, and / or combinations thereof. These various implementations can include implementation in one or more computer programs that can be executed and / or interpreted on a programmable system that includes at least one programmable processor, which can be special purpose or general purpose, coupled to receive data and instructions from a storage system, at least one input device, and at least one output device, and to transmit data and instructions to the storage system, at least one input device, and at least one output device.

[0238] A software application (i.e., a software resource) may refer to computer software that enables a computing device to perform tasks. In some examples, a software application may be referred to as an "application," "app," or "program." Example applications include, but are not limited to, system diagnostic applications, system management applications, system maintenance applications, word processing applications, spreadsheet applications, messaging applications, media streaming applications, social networking applications, and gaming applications.

[0239] These computer programs (also referred to as programs, software, software applications, or code) include machine instructions for a programmable processor and may be implemented in high-level procedural and / or object-oriented programming languages ​​and / or assembly / machine languages. As used herein, the terms "machine-readable medium" and "computer-readable medium" refer to any computer program product, non-transitory computer-readable medium, apparatus, and / or device (e.g., disk, optical disk, memory, programmable logic device (PLD)) for providing machine instructions and / or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. The term "machine-readable signal" refers to any signal for providing machine instructions and / or data to a programmable processor.

[0240] The processes and logic flows described in this specification can be performed by one or more programmable processors (also known as data processing hardware) to execute one or more computer programs to perform functions by operating input data and generating output. These processes and logic flows can also be performed by dedicated logic circuits (such as FPGA (field programmable gate array) or ASIC (application-specific integrated circuit)). Processors suitable for executing computer programs include, for example, general-purpose and special-purpose microprocessors, and one or more processors of any type of digital computer. Typically, the processor will receive instructions and data from a read-only memory or a random access memory or both. The basic elements of a computer are a processor for executing instructions and one or more storage devices for storing instructions and data. Typically, a computer will also include or be operably connected to receive data from or transfer data to one or more large-capacity storage devices (such as magnetic disks, magneto-optical disks, or optical disks) for storing data, or both. However, a computer does not need to have such a device. Computer-readable media suitable for storing computer program instructions and data include all forms of non-volatile memory, media, and memory devices, including, for example, semiconductor memory devices, such as EPROM, EEPROM, and flash memory devices; magnetic disks, such as internal hard disks or removable disks; magneto-optical disks; and CDROM and DVD-ROM disks. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.

[0241] To provide interaction with a user, one or more aspects of the present disclosure may be implemented on a computer having a display device for displaying information to the user, such as a CRT (cathode ray tube), LCD (liquid crystal display) monitor, or touch screen, and optionally a keyboard and pointing device, such as a mouse or trackball, through which the user can provide input to the computer. Other types of devices may also be used to provide interaction with the user; for example, feedback provided to the user may be any form of sensory feedback, such as visual feedback, auditory feedback, or tactile feedback; and input from the user may be received in any form, including sound, voice, or tactile input. In addition, the computer may interact with the user by sending documents to and receiving documents from a device used by the user; for example, by sending a web page to a web browser of a user's client device in response to a request received from the web browser.

[0242] Further aspects and embodiments of the invention are described below.

[0243] In one aspect, described herein is a method of using a myosin inhibitor to treat a patient in need thereof, comprising:

[0244] administering to the patient an initial dose of a myosin inhibitor for a first treatment period;

[0245] administering a first reduced dose of the myosin inhibitor to the patient during a second treatment period when a first measure of left ventricular outflow tract obstruction in the patient taken at or near the end of the first treatment period is below a threshold, wherein the first reduced dose is less than the starting dose; and

[0246] When a second measure of left ventricular outflow tract obstruction of the patient taken at or near the end of the second treatment period is below a threshold, a second reduced dose of the myosin inhibitor is administered to the patient during a third treatment period, wherein the second reduced dose is less than the dose of the myosin inhibitor administered immediately prior to the second reduced dose.

[0247] In some embodiments, the method further comprises:

[0248] obtaining a first measure of left ventricular outflow tract obstruction in the patient taken at or near the end of the first treatment period; and

[0249] A second measure of left ventricular outflow tract obstruction of the patient is obtained, taken at or near the end of the second treatment period.

[0250] In some embodiments, the second treatment period immediately follows the first treatment period.

[0251] In some embodiments, the third treatment period immediately follows the second treatment period.

[0252] In some embodiments, the dose of the myosin inhibitor administered to the patient is not increased until after the third treatment period.

[0253] In some embodiments, the first measurement and the second measurement are taken using echocardiography.

[0254] In some embodiments, the first measure of left ventricular outflow tract obstruction is a measure of the Valsalva LVOT gradient.

[0255] In some embodiments, the second measure of left ventricular outflow tract obstruction is a measure of the Valsalva LVOT gradient.

[0256] In some embodiments, the threshold is a Valsalva LVOT gradient of 20 mmHg.

[0257] In some embodiments, the patient has a reduced risk of an adverse event compared to continuing to administer the myosin inhibitor at the starting dose.

[0258] In some embodiments, the first treatment period is about 4 weeks.

[0259] In some embodiments, the second treatment period is about 4 weeks.

[0260] In some embodiments, the first, second, and third treatment periods are each about 4 weeks.

[0261] In some embodiments, the patient suffers from symptomatic obstructive hypertrophic cardiomyopathy.

[0262] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy.

[0263] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), mavaketide, MYK-581, afuketide, and pharmaceutically acceptable salts thereof.

[0264] In some embodiments, the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the myosin inhibitor is mavacetel.

[0266] In some embodiments, the starting dose is about 5 mg of mavacetel per day.

[0267] In some embodiments, the first reduced dose is less than about 5 mg of mavacetel per day.

[0268] In some embodiments, the first reduced dose is selected from the group consisting of about 2.5 mg of mavaketal per day, about 1 mg of mavaketal per day, or 0 mg of mavaketal per day.

[0269] In some embodiments, the second reduced dose is about 1 mg of mavaketal per day or 0 mg of mavaketal per day.

[0270] In some embodiments, the first reduced dose is about 2.5 mg of mavaketal per day and the second reduced dose is 0 mg of mavaketal per day.

[0271] In some embodiments, the patient's left ventricular ejection fraction is greater than or equal to about 50% at or near the end of the first treatment period and the second treatment period.

[0272] Another aspect disclosed herein is a method of treating symptomatic obstructive hypertrophic cardiomyopathy in a patient in need thereof, comprising:

[0273] administering to the patient a starting dose of 5 mg of mavacetide per day for a first treatment period, wherein the first treatment period is about 4 weeks;

[0274] When the patient's Valsalva left ventricular outflow tract (LVOT) gradient taken at or near the end of the first treatment period is less than 20 mmHg, administering 2.5 mg of mavaketide per day to the patient for a second treatment period, wherein the second treatment period is about 4 weeks; and

[0275] When the patient's Valsalva left ventricular outflow tract (LVOT) gradient taken at or near the end of the second treatment period is less than 20 mmHg, the patient is administered 0 mg of mavacetate per day for a third treatment period, wherein the third treatment period is about 4 weeks.

[0276] In some embodiments, the second treatment period immediately follows the first treatment period.

[0277] In some embodiments, the third treatment period immediately follows the second treatment period.

[0278] In some embodiments, the method further comprises administering 2.5 mg of mavaketide per day to the patient for a fourth treatment period when the patient's left ventricular ejection fraction measurement taken at or near the end of the third treatment period is greater than or equal to about 50%, wherein the fourth treatment period is about 4 weeks.

[0279] In some embodiments, the fourth treatment period immediately follows the third treatment period.

[0280] In some embodiments, the patient's LVEF is greater than or equal to about 50%.

[0281] Another aspect described herein is a method of using a myosin inhibitor to treat a patient in need thereof, the method comprising the steps of:

[0282] (a) administering an initial dose of myosin inhibitor during a first treatment period;

[0283] (b) assessing left ventricular outflow tract obstruction in the patient to obtain a first assessment result and determining whether the first assessment result is below a first threshold;

[0284] (c) administering a second dose during a second treatment period when the first assessment result is below a first threshold, wherein the second dose is less than the starting dose;

[0285] (d) assessing the patient's left ventricular outflow tract obstruction to obtain a second assessment result and determining whether the second assessment result is below a second threshold; and

[0286] (e) when the second assessment result is below a second threshold, administering a third dose during a third treatment period, wherein the third dose is less than the second dose.

[0287] In some embodiments, the method further comprises the following steps:

[0288] (f) at or near the end of the third treatment period, assessing left ventricular outflow tract obstruction of the patient to obtain a third assessment result and determining whether the third assessment result is greater than or equal to a third threshold, and assessing the patient's left ventricular ejection fraction (LVEF); and

[0289] (g) administering a fourth dose during a fourth treatment period when the third assessment result is greater than or equal to a third threshold and the LVEF of the patient is greater than or equal to a LVEF threshold, wherein the fourth dose is greater than the third dose.

[0290] In some embodiments, the method further comprises the following steps:

[0291] (f) assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the third treatment period; and

[0292] (g) administering a fourth dose during a fourth treatment period when the patient's LVEF is greater than or equal to a safety threshold, wherein the fourth dose is greater than the third dose.

[0293] In some embodiments, the method further comprises the following steps:

[0294] (h) at or near the end of the fourth treatment period, assessing the patient's left ventricular outflow tract obstruction to obtain a fourth assessment result and determining whether the fourth assessment result is greater than or equal to the fourth threshold, and assessing the patient's left ventricular ejection fraction (LVEF); and

[0295] (i) when the fourth assessment result is greater than or equal to the fourth threshold and the LVEF of the patient is greater than or equal to the LVEF threshold, administering the fifth dose during a fifth treatment period, wherein the fifth dose is greater than the fourth dose.

[0296] In some embodiments, the first assessment and the second assessment are performed by non-invasive techniques.

[0297] In some embodiments, the third assessment is performed by non-invasive techniques.

[0298] In some embodiments, non-invasive techniques include echocardiography.

[0299] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0300] In some embodiments, non-invasive techniques include measuring the LVOT gradient using the Valsalva maneuver.

[0301] In some embodiments, the first assessment result is a first Valsalva LVOT gradient and the second assessment result is a second Valsalva LVOT gradient.

[0302] In some embodiments, the first threshold and the second threshold are each a Valsalva LVOT gradient.

[0303] In some embodiments, the first threshold and the second threshold are each a Valsalva LVOT gradient of 20 mmHg.

[0304] In some embodiments, the methods reduce the risk of adverse events.

[0305] In some embodiments, the adverse event is systolic dysfunction.

[0306] In some embodiments, the adverse event is heart failure.

[0307] In some embodiments, the patient has a reduced risk of an adverse event compared to continuing to administer the myosin inhibitor at the starting dose.

[0308] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), mavaketide, MYK-581, and afukide, and pharmaceutically acceptable salts thereof.

[0309] In some embodiments, the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the myosin inhibitor is mavacetel.

[0311] In some embodiments, the starting dose is 5 mg of mavacetel per day.

[0312] In some embodiments, the second dose is less than 5 mg of mavacetel per day.

[0313] In some embodiments, the second dose is 2.5 mg of mavacetel per day.

[0314] In some embodiments, the third dose is less than 2.5 mg of mavacetel per day.

[0315] In some embodiments, the third reduced dose is 0 mg of mavaketal per day or 1 mg of mavaketal per day.

[0316] In some embodiments, the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

[0317] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

[0318] In some embodiments, a dose of 0 mg is administered during the third treatment period.

[0319] In some embodiments, the dose of the myosin inhibitor administered to the patient is not increased until after the third treatment period.

[0320] In some embodiments, the LVEF threshold is 55%.

[0321] In some embodiments, the safety threshold is 50%.

[0322] In some embodiments, the method further comprises assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the first treatment period and at or near the end of the second treatment period.

[0323] In some embodiments, the method further comprises temporarily stopping treatment when the LVEF assessment at or near the end of the first treatment period or the second treatment period is less than 50%.

[0324] In some embodiments, the first treatment period is about four weeks and the second treatment period is about four weeks.

[0325] In some embodiments, the first treatment period is about four weeks, the second treatment period is about four weeks, and the third treatment period is about four weeks.

[0326] Another aspect disclosed herein is a method of using Mavaketide to treat a patient in need thereof, the method comprising the steps of:

[0327] (a) during a first treatment period, administering 5 mg of mavacetide per day to the patient;

[0328] (b) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient;

[0329] (c) administering 2.5 mg of mavacetide per day to said patient daily during a second treatment period when said first Valsalva LVOT gradient is less than 20 mmHg;

[0330] (d) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a second Valsalva LVOT gradient; and

[0331] (e) when the second Valsalva LVOT gradient is less than 20 mmHg, administering 0 mg or 1 mg of Mavaketide daily to the patient for a third treatment period.

[0332] In some embodiments, the method further comprises the following steps:

[0333] (f) at or near the end of the third treatment period, assessing the patient's LVOT gradient using a Valsalva maneuver to determine a third Valsalva LVOT gradient and assessing the patient's left ventricular ejection fraction (LVEF); and

[0334] (g) when the patient's third Valsalva LVOT gradient is greater than or equal to 30 mmHg and the LVEF is greater than or equal to 55%, administering 2.5 mg of mavacetide daily to the patient for a fourth treatment period.

[0335] In some embodiments, the method further comprises the following steps:

[0336] (f) assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the third treatment period; and

[0337] (g) When the patient's LVEF is greater than or equal to 50%, the patient is administered 2.5 mg of Mavaketide daily for a fourth treatment period.

[0338] In some embodiments, the method further comprises the following steps:

[0339] (h) at or near the end of the fourth treatment period, assessing the patient's LVOT gradient using a Valsalva maneuver to determine a fourth Valsalva LVOT gradient and assessing the patient's left ventricular ejection fraction (LVEF); and

[0340] (i) When the patient's fourth Valsalva LVOT gradient is greater than or equal to 30 mmHg and LVEF is greater than or equal to 55%, administering 5 mg of Mavaketide daily to the patient for a fifth treatment period.

[0341] Another aspect disclosed herein is a method of administering mavacetal to a patient, wherein the patient suffers from oHCM, the method comprising the steps of:

[0342] (a) administering to the patient a starting dose of 5 mg of mavacetide per day for a first treatment period;

[0343] (b) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient;

[0344] (c) when the first Valsalva LVOT gradient is less than 20 mmHg, administering 2.5 mg of Mavaketide per day to the patient for a second treatment period;

[0345] (d) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a second Valsalva LVOT gradient;

[0346] (e) when the second Valsalva LVOT gradient is less than 20 mmHg, administering 0 mg of mavacetide per day to the patient for a third treatment period;

[0347] (f) evaluating the patient to determine a first left ventricular ejection fraction (LVEF); and

[0348] (g) when the first LVEF is greater than or equal to 50%, administering 2.5 mg of mavacetir per day to the patient for a fourth treatment period.

[0349] In some embodiments, the method further comprises the following steps:

[0350] (h) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a third Valsalva LVOT gradient, and evaluating the patient to determine a second left ventricular ejection fraction (LVEF); and

[0351] (i) when the third Valsalva LVOT gradient is greater than or equal to 30 mmHg and the second LVEF is greater than or equal to 55%, administering 5 mg of mavacetide per day to the patient for a fifth treatment period.

[0352] In some embodiments, the patient's risk of contractile dysfunction and / or heart failure is reduced compared to continuing to administer the myosin inhibitor at the starting dose.

[0353] In some embodiments, the first treatment period is about four weeks and the second treatment period is about four weeks.

[0354] In some embodiments, the third treatment period is about four weeks.

[0355] In some embodiments, the fourth treatment period is about twelve weeks.

[0356] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

[0357] Another aspect disclosed herein is a method of administering mavacetal to a patient, wherein the patient suffers from oHCM, the method comprising the steps of:

[0358] administering to the patient a starting dose of 5 mg of mavacetide per day for a first treatment period;

[0359] assessing the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient;

[0360] administering a second dose of mavacetel during a second treatment period, wherein if the first Valsalva LVOT gradient is less than 20 mmHg, the second dose is 2.5 mg per day, and wherein if the first Valsalva LVOT gradient is greater than or equal to 20 mmHg, the second dose is 5 mg per day;

[0361] Assess the patient's LVOT gradient using the Valsalva maneuver to determine the second Valsalva LVOT gradient;

[0362] A third dose of Mavaketide is administered during the third treatment period, wherein if the second Valsalva LVOT gradient is less than 20 mmHg, the third dose is less than the second dose, and the third dose is 2.5 mg, 1 mg, or 0 mg per day; and wherein if the first Valsalva LVOT gradient is greater than or equal to 20 mmHg, the third dose is the same as the second dose, and the third dose is 5 mg or 2.5 mg per day.

[0363] In some embodiments, the patient receives a third dose of 0 mg per day during the third treatment period; the method further comprises the steps of:

[0364] Assess the patient to determine the primary left ventricular ejection fraction (LVEF); and

[0365] A fourth dose of mavacetel is administered during the fourth treatment period, wherein if the first LVEF is greater than or equal to 50%, the fourth dose is 2.5 mg per day, and wherein if the first LVEF is less than 50%, the fourth dose is 0 mg per day.

[0366] In some embodiments, the patient receives a third dose of 1 mg per day, 2.5 mg per day, or 5 mg per day during the third treatment period; the method further comprises the following steps:

[0367] Assessing the patient's LVOT gradient using the Valsalva maneuver to determine a third Valsalva LVOT gradient and assessing the patient to determine a first left ventricular ejection fraction (LVEF); and

[0368] A fourth dose of Mavaketide is administered during the fourth treatment period, wherein if the third Valsalva LVOT gradient is greater than or equal to 30 mmHg and the first LVEF is greater than or equal to 55%, the fourth dose is greater than the third dose and the fourth dose is 2.5 mg, 5 mg, or 10 mg per day, and wherein if the third Valsalva LVOT gradient is less than 30 mmHg or the first LVEF is less than 55%, the fourth dose is the same as the third dose and the fourth dose is 1 mg, 2.5 mg, or 5 mg per day.

[0369] In some embodiments, the patient's risk of systolic dysfunction and / or heart failure is reduced compared to continuing to administer mavaketide at the starting dose.

[0370] In some embodiments, the first treatment period is about four weeks and the second treatment period is about four weeks.

[0371] In some embodiments, the third treatment period is about four weeks.

[0372] In some embodiments, the fourth treatment period is about twelve weeks.

[0373] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

[0374] Another aspect disclosed herein is a method of treating a patient in need thereof using a myosin inhibitor, comprising:

[0375] administering to the patient an initial dose of a myosin inhibitor for a first treatment period;

[0376] A second dose of a myosin inhibitor is administered to the patient for a second treatment period, wherein:

[0377] The second dose is less than the starting dose if the patient's LVOT gradient taken at or near the end of the first treatment period is below a threshold, and

[0378] If the patient's LVOT gradient taken at or near the end of the first treatment period is greater than or equal to the threshold, the second dose is the same as the starting dose; and

[0379] A third dose of the myosin inhibitor is administered to the patient for a third treatment period, wherein:

[0380] The third dose is less than the second dose if the patient's LVOT gradient taken at or near the end of the second treatment period is below the threshold, and

[0381] If the patient's LVOT gradient taken at or near the end of the second treatment period is greater than or equal to the threshold, the third dose is the same as the second dose.

[0382] In some embodiments, the second treatment period immediately follows the third treatment period.

[0383] In some embodiments, the third treatment period immediately follows the second treatment period.

[0384] In some embodiments, the method further comprises administering to the patient a fourth dose of a myosin inhibitor for a fourth treatment period, wherein:

[0385] If the third dose is less than the second dose, and the second dose is less than the starting dose, and a measurement of the patient's left ventricular ejection fraction taken at or near the end of the third treatment period is greater than or equal to about 50%, then the fourth dose is the same as the lowest dose previously administered and the fourth treatment period, and

[0386] If the third dose is equal to the second dose and / or the second dose is equal to the starting dose, the fourth treatment period is longer than the third treatment period.

[0387] In some embodiments, the fourth treatment period immediately follows the third treatment period.

[0388] In some embodiments, the first treatment period, the second treatment period, and the third treatment period are about four weeks.

[0389] In some embodiments, the threshold value is 20 mmHg.

[0390] In some embodiments, when the third dose is less than the second dose and the second dose is less than the starting dose, and the patient's LVEF measurement taken at or near the end of the third treatment period is greater than or equal to about 50%, the fourth treatment period is about 4 weeks.

[0391] In some embodiments, when the third dose is equal to the second dose and / or the second dose is equal to the starting dose, the fourth treatment period is about 12 weeks.

[0392] In some embodiments, the patient's LVEF is greater than or equal to about 50%.

[0393] In some embodiments, the LVOT gradient is a Valsalva LVOT gradient.

[0394] In some embodiments, the patient has a reduced risk of an adverse event compared to continuing to administer the myosin inhibitor at the starting dose.

[0395] In some embodiments, the first, second, and third treatment periods are each about 4 weeks.

[0396] In some embodiments, the patient suffers from symptomatic obstructive hypertrophic cardiomyopathy.

[0397] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy.

[0398] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), mavaketide, MYK-581, afuketide, and pharmaceutically acceptable salts thereof.

[0399] In some embodiments, the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

[0400] In some embodiments, the myosin inhibitor is mavacetel.

[0401] In some embodiments, the starting dose is about 5 mg of mavacetel per day.

[0402] In some embodiments, the second dose is less than about 5 mg of mavacetel per day.

[0403] In some embodiments, the third dose is less than about 2.5 mg of mavacetel per day.

[0404] In some embodiments, the second dose is selected from the group consisting of about 2.5 mg of mavaketal per day, about 1 mg of mavaketal per day, or 0 mg of mavaketal per day.

[0405] In some embodiments, the third dose is about 1 mg of mavaketal per day or 0 mg of mavaketal per day.

[0406] In some embodiments, the second dose is about 2.5 mg of mavaketal per day, and the third dose is 0 mg of mavaketal per day.

[0407] In some embodiments, the fourth dose is selected from the group consisting of 2.5 mg, 5 mg, and 10 mg of mavacetel per day.

[0408] Also disclosed herein is a method of using a myosin inhibitor to treat a patient in need thereof, the method comprising:

[0409] Administer a starting dose of myosin inhibitor at least once daily at the beginning of the initiation phase; and

[0410] performing one or more assessments of left ventricular outflow tract obstruction in the patient during the initiation phase to obtain one or more assessment results; and

[0411] Administration of the myosin inhibitor is discontinued based on the one or more evaluation results.

[0412] In some embodiments, the method further comprises resuming administration of the myosin inhibitor after cessation.

[0413] In some embodiments, administration is resumed after assessing the patient's LVEF, wherein administration is resumed when the LVEF is greater than or equal to a safety threshold.

[0414] In some embodiments, one or more assessments are performed by non-invasive techniques.

[0415] In some embodiments, non-invasive techniques include echocardiography.

[0416] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0417] In some embodiments, the non-invasive technique includes measuring LVOT gradients using a Valsalva maneuver, and the one or more assessment results are one or more Valsalva LVOT gradients.

[0418] In some embodiments, the method comprises stopping administration of the myosin inhibitor when the Valsalva LVOT gradient is less than 20 mmHg.

[0419] In some embodiments, the method includes assessing the patient's left ventricular outflow tract obstruction two or more times by non-invasive techniques during the initiation phase to obtain two or more assessment results.

[0420] In some embodiments, the non-invasive technique includes measuring the LVOT gradient using a Valsalva maneuver, and the two or more assessment results are two or more Valsalva LVOT gradients.

[0421] In some embodiments, the method comprises stopping administration of the myosin inhibitor when at least two of the two or more Valsalva LVOT gradients are below 20 mmHg.

[0422] In some embodiments, the methods reduce the risk of adverse events in the patient.

[0423] In some embodiments, the adverse event is systolic dysfunction.

[0424] In some embodiments, the adverse event is heart failure.

[0425] In some embodiments, the patient has a reduced risk of an adverse event compared to continued administration of the myosin inhibitor.

[0426] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), mavaketide, MYK-581, and afukate, optionally in the form of pharmaceutically acceptable salts thereof.

[0427] In some embodiments, the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

[0428] In some embodiments, the myosin inhibitor is mavacetel.

[0429] In some embodiments, the starting dose is 5 mg of mavacetel per day.

[0430] In some embodiments, the patient suffers from oHCM.

[0431] In some embodiments, the duration of the initial phase is from about 4 weeks to about 6 months.

[0432] In some embodiments, the duration of the initial phase is from about 8 weeks to about 16 weeks.

[0433] In some embodiments, the safety threshold is 50%.

[0434] Also disclosed herein is a method of using Mavaketal to treat a patient in need thereof, comprising the following steps:

[0435] (a) at the beginning of the initiation phase, administering to the patient a starting dose of 5 mg per day of Mavaketide; and

[0436] (b) assessing the patient's LVOT gradient two or more times at separate times during the initial phase using the Valsalva maneuver to obtain two or more Valsalva LVOT gradients; and

[0437] (c) when each of the two or more Valsalva LVOT gradients is less than 20 mmHg, discontinuing administration of Mavaketel.

[0438] Another aspect disclosed herein is a method of using a myosin inhibitor to treat a patient in need thereof, the method comprising:

[0439] administering to said patient an initial dose of said myosin inhibitor;

[0440] assessing said patient for left ventricular outflow tract obstruction at or near the end of two or more separate treatment periods to obtain two or more assessments; and

[0441] A first reduced dose and subsequently a second reduced dose are administered based on the two or more assessment results, wherein the assessment results are below a threshold, wherein the first reduced dose is less than the starting dose, and the second reduced dose is less than the first reduced dose.

[0442] In some embodiments, the dose of myosin inhibitor administered to the patient is not increased until two or more assessments are completed at or near the end of two or more separate treatment periods.

[0443] In some embodiments, the two or more assessments are performed by non-invasive techniques.

[0444] In some embodiments, non-invasive techniques include echocardiography.

[0445] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0446] In some embodiments, non-invasive techniques include measuring the LVOT gradient using the Valsalva maneuver.

[0447] In some embodiments, the assessment outcome is the Valsalva LVOT gradient.

[0448] In some embodiments, the threshold is the Valsalva LVOT gradient.

[0449] In some embodiments, the threshold is a Valsalva LVOT gradient of 20 mmHg.

[0450] In some embodiments, the methods reduce the risk of adverse events.

[0451] In some embodiments, the adverse event is systolic dysfunction.

[0452] In some embodiments, the adverse event is heart failure.

[0453] In some embodiments, the patient has a reduced risk of an adverse event compared to continuing to administer the myosin inhibitor at the starting dose.

[0454] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), mavaketide, MYK-581, afuketide, and pharmaceutically acceptable salts thereof.

[0455] In some embodiments, the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

[0456] In some embodiments, the myosin inhibitor is mavacetel.

[0457] In some embodiments, the starting dose is 5 mg of mavacetel per day.

[0458] In some embodiments, the first reduced dose is less than 5 mg per day.

[0459] In some embodiments, the second reduced dose is less than 2.5 mg per day.

[0460] In some embodiments, the first reduced dose is 2.5 mg of mavacetel per day.

[0461] In some embodiments, the second reduced dose is 1 mg per day or 0 mg per day of mavacetel.

[0462] In some embodiments, the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

[0463] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

[0464] In some embodiments, the two or more separate treatment periods include a first treatment period and a second treatment period, and wherein the two or more evaluation results include a first evaluation result at or near the end of the first treatment period and a second evaluation result at or near the end of the second treatment period.

[0465] In some embodiments, the method further comprises administering a myosin inhibitor for a third treatment period after the second assessment.

[0466] In some embodiments, the dose of the myosin inhibitor administered to the patient is not increased until after the third treatment period.

[0467] In some embodiments, the first treatment period is about four weeks and the second treatment period is about four weeks.

[0468] In some embodiments, the third treatment period is about four weeks.

[0469] In some embodiments, the method includes assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of two or more separate treatment periods.

[0470] Another aspect disclosed herein is a method of reducing the risk of heart failure with reduced ejection fraction resulting from administration of a myosin inhibitor to a patient, the method comprising the steps of:

[0471] administering a myosin inhibitor to said patient;

[0472] Temporarily stopping the administration of the myosin inhibitor when the patient's LVEF is less than 50%;

[0473] When the patient's LVEF is greater than or equal to 50%, resuming administration of the myosin inhibitor to the patient; and

[0474] When the patient's LVEF was less than 50% after resumption of administration, administration of the myosin inhibitor was permanently discontinued.

[0475] In some embodiments, LVEF is determined by non-invasive techniques.

[0476] In some embodiments, the non-invasive technique is echocardiography.

[0477] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0478] In some embodiments, resuming administration comprises administering the same dose that the patient received prior to the temporary discontinuation.

[0479] In some embodiments, resuming administration comprises administering a dose that is lower than the dose the patient received prior to the temporary cessation.

[0480] In some embodiments, resuming administration comprises administering a minimum dose of the myosin inhibitor to the patient, wherein the minimum dose is the lowest dose of the myosin inhibitor approved by a government regulatory agency for administration to the patient.

[0481] In some embodiments, the government regulatory agency is an agency in the United States, European Union, Switzerland, Japan, China, South Korea, Canada, Mexico, Australia, New Zealand, Brazil, Russia, Ukraine, Georgia, Vietnam, Singapore, Malaysia, Philippines, India, Indonesia, Israel, South Africa, Colombia, Costa Rica, Dominican Republic, Ecuador, Guatemala, El Salvador, Honduras, Egypt, Syria, Algeria, Kenya, Morocco, or Nigeria.

[0482] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), mavaketide, MYK-581, and afukide, and pharmaceutically acceptable salts thereof.

[0483] In some embodiments, the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

[0484] In some embodiments, the myosin inhibitor is mavacetel.

[0485] 171. In some embodiments, the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

[0486] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

[0487] Also disclosed herein is a method of reducing the risk of heart failure with reduced ejection fraction resulting from administration of mavaketide to a patient, the method comprising the steps of:

[0488] administering Mavaketide to the patient at a dose of 2.5 mg per day;

[0489] When the patient's LVEF is less than 50%, temporarily stop the administration of Mavaketide;

[0490] When the patient's LVEF is greater than or equal to 50%, resuming administration of mavaketide to the patient at a dose of 2.5 mg per day; and

[0491] When the patient's LVEF was less than 50% after resumption of dosing, mavacetal was permanently discontinued.

[0492] Also disclosed herein are methods of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of mavaketide, wherein the patient is not receiving concomitant administration of a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer.

[0493] Also disclosed herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, wherein the patient is being treated with a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer, the method comprising:

[0494] discontinuing administration of the strong or moderate CYP2C19 inducer or the strong or moderate CYP3A4 inducer to the patient; and

[0495] A therapeutically effective amount of mavaketide is administered to the patient, thereby avoiding the use of mavaketide in combination with a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer.

[0496] Another aspect disclosed herein is a method of administering a myosin inhibitor to a patient initiating concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor while receiving myosin inhibitor therapy, the method comprising:

[0497] administering a first daily dose of the myosin inhibitor during a first treatment period prior to initiating concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor;

[0498] A second daily dose of the myosin inhibitor is administered during a second treatment period, the second daily dose being less than the first daily dose, wherein the patient is receiving concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor during the second treatment period.

[0499] In some embodiments, the method further comprises assessing the patient's LVEF during the second treatment period, and temporarily stopping administration of the myosin inhibitor if the LVEF is below a safety threshold.

[0500] In some embodiments, the safety threshold is 50%.

[0501] In some embodiments, the method further comprises assessing the patient's LVEF and LVOT gradient after cessation of administration, and resuming administration of the first daily dose when the LVOT gradient is greater than or equal to a threshold and the LVEF is greater than or equal to a LVEF threshold.

[0502] In some embodiments, the threshold is 30 mmHg and the LVEF threshold is 55%.

[0503] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), mavaketide, MYK-581, and afukide, and pharmaceutically acceptable salts thereof.

[0504] In some embodiments, the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

[0505] In some embodiments, the myosin inhibitor is mavacetel.

[0506] In some embodiments, the first daily dose is 5 mg, 10 mg, or 15 mg of mavaketel and the second daily dose is 2.5 mg, 5 mg, or 10 mg of mavaketel.

[0507] In some embodiments, the weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor is selected from the group consisting of cimetidine, ciprofloxacin, diltiazem, felbamate, omeprazole at a dose of 20 mg once daily, isoniazid, fluconazole, and verapamil.

[0508] In some embodiments, the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

[0509] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

[0510] In some embodiments, assessing the patient's LVEF during the second treatment period comprises assessing the patient's LVEF about four weeks after initiating concomitant therapy.

[0511] In some embodiments, the second treatment period is at least 12 weeks, and wherein the second daily dosage is not increased to a higher dose during at least the first 12 weeks of the second treatment period.

[0512] Another aspect disclosed herein is a method of treating HCM in a patient being administered a first daily dose of mavaketide, wherein the patient then requires concomitant treatment with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor in addition to mavaketide, the method comprising:

[0513] In addition to administration of the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, the patient is administered a second daily dose of mavacetide that is less than the first daily dose.

[0514] In some embodiments, the first daily dose is 5 mg, 10 mg, or 15 mg per day and the second daily dose is 2.5 mg, 5 mg, or 10 mg per day.

[0515] Another aspect disclosed herein is a method of initiating concomitant administration of mavaketide to a patient who is being administered a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, wherein the patient requires concomitant administration of mavaketide and the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, and wherein the patient is receiving a stable therapy with the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, the method comprising:

[0516] The patient is concomitantly administered mavacetide at a daily dose of 5 mg per day and a stable therapy of the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor.

[0517] Another aspect disclosed herein is a method of administering a myosin inhibitor to a patient initiating or increasing the dose of concomitant therapy with a negative inotropic agent while receiving myosin inhibitor therapy, the method comprising:

[0518] (a) administering a therapeutically effective amount of a myosin inhibitor during a first treatment period;

[0519] (b) continuing to administer the myosin inhibitor during a second treatment period, wherein during the second treatment period the patient initiates or increases the dose of concomitant therapy with a negative inotropic drug; and

[0520] (c) providing echocardiographic monitoring of LVEF during said second treatment period.

[0521] In some embodiments, echocardiographic monitoring of LVEF is provided until a stable dose and clinical response is achieved.

[0522] In some embodiments, the method further comprises providing close medical supervision during the second treatment period.

[0523] In some embodiments, the myosin inhibitor is mavacetel.

[0524] Another aspect disclosed herein is a computer-implemented method that, when executed by data processing hardware, causes the data processing hardware to perform operations including:

[0525] obtaining healthcare professional (HCP) evaluation records associated with the patient, the HCP evaluation records including the outcome of the procedure;

[0526] using the HCP assessment record to determine whether the patient is authorized to receive a prescription authorization authorizing the use of a prescription medication; and

[0527] When the patient is authorized to receive the prescribed medication:

[0528] obtaining a pharmacy assessment record associated with the patient, the pharmacy assessment record including a medical condition of the patient;

[0529] using the pharmacy assessment record to determine whether the pharmacy is authorized to dispense the prescription medication to the patient; and

[0530] When the pharmacy is authorized to dispense the prescribed medication to the patient:

[0531] Generate dispensing authorizations; and

[0532] The dispensing authorization is transmitted to the pharmacy.

[0533] In some embodiments, the procedural results include echocardiographic results.

[0534] In some embodiments, at least one of the HCP assessment record and the pharmacy assessment record includes potential drug-drug interactions.

[0535] In some embodiments, obtaining the HCP assessment record includes retrieving the HCP assessment record from a database remote from the data processing hardware.

[0536] In some embodiments, determining whether the patient is authorized to receive prescription authorization is in response to receiving a prescription request.

[0537] In some embodiments, the authorization to dispense a medication includes:

[0538] the amount of the prescribed medication that the patient is authorized to receive; and

[0539] The time period during which the patient is authorized to receive the prescribed medication.

[0540] In some embodiments, the operations further include, after the period of time has elapsed:

[0541] determining whether updated procedural results relevant to the patient are available;

[0542] updating the dispensing authorization using the updated procedure results when the updated procedure results are available; and

[0543] When the updated procedure result is not available, renewing the dispensing authorization is denied.

[0544] In some embodiments, updating the dispensing authorization includes at least one of the following:

[0545] adjusting the amount of the prescribed medication that the patient is authorized to receive; and

[0546] The time period during which the patient is authorized to receive the prescribed medication is adjusted.

[0547] In some embodiments, the operations further include generating a report for a regulatory agency when the patient is not authorized to receive the prescribed medication or when the pharmacy is not authorized to dispense the prescribed medication to the patient.

[0548] In some embodiments, the prescription medication includes mavacetal.

[0549] The present invention also discloses a system comprising:

[0550] data processing hardware; and

[0551] Memory hardware in communication with the data processing hardware, the memory hardware storing instructions that, when executed on the data processing hardware, cause the data processing hardware to perform the operations described above.

[0552] Also disclosed herein is a method of reducing the risk of heart failure due to contractile dysfunction in a patient being administered a myosin inhibitor, comprising:

[0553] providing a data storage facility, the data storage facility comprising a database containing patient HCP assessment records and patient pharmacy assessment records, wherein each patient HCP assessment record comprises information regarding said patient's echocardiogram date, LVEF determined from said echocardiogram, VLVOT determined from said echocardiogram, experience of a clinical heart failure event, and risk of potential drug-drug interactions, and wherein each patient pharmacy assessment record comprises information regarding said patient's medical condition, concomitant medications and supplements, and potential drug-drug interactions;

[0554] A central controller having one or more processors coupled to a communications network is provided, the central controller being coupled to the data storage facility to read data from and write data to the data storage facility over the network, wherein:

[0555] The central controller controls the transmission of data to and reception of data from the data storage facility via the network,

[0556] the central controller being programmed to output, via the network, an HCP authorization to prescribe the myosin inhibitor for the patient, wherein output of the HCP authorization is contingent upon satisfactory HCP information entered into each patient's HCP evaluation record regarding echocardiogram date, echocardiogram results, clinical heart failure event experience, and risk of drug-drug interactions, and wherein the central controller prevents output of the HCP authorization due to unsatisfactory HCP information,

[0557] The central controller is further programmed to output a dispensing authorization for the myosin inhibitor to the patient via the network, wherein the output of the pharmacy authorization is contingent upon the output of the HCP authorization and satisfactory pharmacy information entered into each patient's pharmacy assessment record regarding the patient's medical condition, concomitant medications and supplements, and potential drug-drug interactions, and wherein the central controller prevents the output of the dispensing authorization due to unsatisfactory pharmacy information and / or lack of HCP authorization, and

[0558] Therein, the central controller manages one or more aspects of reporting unsatisfactory information regarding clinical heart failure event experience to a regulatory agency or other supervisory body.

[0559] Also disclosed herein is a computer-implemented method that, when executed by data processing hardware, causes the data processing hardware to perform operations including:

[0560] obtaining healthcare professional (HCP) evaluation records associated with the patient, the HCP evaluation records including the outcome of the procedure;

[0561] obtaining a pharmacy assessment record associated with the patient, the pharmacy assessment record including a medical condition of the patient;

[0562] using the HCP assessment record to determine whether the patient is authorized to receive a prescription authorization authorizing the use of a prescription medication; and

[0563] When the patient is authorized to receive the prescribed medication:

[0564] using the pharmacy assessment record to determine whether the pharmacy is authorized to dispense the prescription medication to the patient; and

[0565] When the pharmacy is authorized to dispense the prescribed medication to the patient:

[0566] Generate dispensing authorizations; and

[0567] The dispensing authorization is transmitted to the pharmacy.

[0568] In some embodiments, the procedural results include echocardiographic results.

[0569] In some embodiments, at least one of the HCP assessment record and the pharmacy assessment record includes potential drug-drug interactions.

[0570] In some embodiments, obtaining the HCP assessment record includes retrieving the HCP assessment record from a database remote from the data processing hardware.

[0571] In some embodiments, determining whether the patient is authorized to receive prescription authorization is in response to receiving a prescription request.

[0572] In some embodiments, the authorization to dispense a medication includes:

[0573] the amount of the prescribed medication that the patient is authorized to receive; and

[0574] The time period during which the patient is authorized to receive the prescribed medication.

[0575] In some embodiments, the operations further include, after the period of time has elapsed:

[0576] determining whether updated procedural results relevant to the patient are available;

[0577] updating the dispensing authorization using the updated procedure results when the updated procedure results are available; and

[0578] When the updated procedure result is not available, renewing the dispensing authorization is denied.

[0579] In some embodiments, updating the dispensing authorization includes at least one of the following:

[0580] adjusting the amount of the prescribed medication that the patient is authorized to receive; and

[0581] The time period during which the patient is authorized to receive the prescribed medication is adjusted.

[0582] In some embodiments, the operations further include generating a report for a regulatory agency when the patient is not authorized to receive the prescribed medication or when the pharmacy is not authorized to dispense the prescribed medication to the patient.

[0583] In some embodiments, the prescription medication includes mavacetal.

[0584] The present invention also discloses a system comprising:

[0585] data processing hardware; and

[0586] Memory hardware in communication with the data processing hardware, the memory hardware storing instructions which, when executed on the data processing hardware, cause the data processing hardware to perform operations described in any one of the above methods.

[0587] Example

[0588] Example 1. Dosage and administration of Mavaketal

[0589] Figure 4-6 The dosing regimen of this embodiment is shown. Figure 4 ) were given an initial dose of 5 mg of mavacetide orally once daily (QD) for 1-4 weeks. During the fourth week, patients were evaluated by echocardiography. Specifically, the patients' Valsalva LVOT gradient and LVEF were determined. Figure 5 If echocardiography at this or any other visit shows an LVEF <50%, interrupt (i.e., temporarily stop) treatment for 4 weeks. After a 4-week interruption in treatment, repeat the echocardiogram and, if the LVEF is ≥50%, resume treatment at one dose level below the previous dose level. Figure 4 At the Week 4 visit, the Valsalva LVOT gradient (VLVOT) was determined, and if the VLVOT was <20 mmHg, the dose was reduced to 2.5 mg QD. If the VLVOT was ≥20 mmHg at the Week 4 visit, the dose was maintained at 5 mg QD.

[0590] Patients will be reassessed by echocardiography 4 weeks later, at the Week 8 visit (during Week 8). Again, if LVEF <50%, treatment will be interrupted (i.e., temporarily stopped) for at least 4 weeks. If VLVOT <20 mmHg, the dose will be reduced - patients receiving 2.5 mg QD will have their dose reduced to 0 mg QD (i.e., medication is suspended), and patients receiving 5 mg QD will have their dose reduced to 2.5 mg QD. If VLVOT ≥20 mmHg, the dose will be maintained (i.e., 2.5 mg QD or 5 mg QD). Therefore, there will be no dose increases at the Week 4 or Week 8 visits.

[0591] Four weeks later, at the 12th week visit (12th 周 During the Week 12 visit), patients will be reassessed by echocardiography. Again, if LVEF is less than 50%, treatment will be interrupted. For patients receiving 5 mg QD or 2.5 mg QD at the Week 12 visit, if LVEF ≥ 55% and VLVOT ≥ 30 mmHg, the dose will be increased by one level. The dose levels are 0 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg (QD). Therefore, for example, a patient receiving 5 mg QD before the Week 12 visit, whose LVEF ≥ 55% and VLVOT ≥ 30 mmHg, will be increased to 10 mg QD after the Week 12 visit. For patients who interrupt / suspend medication (0 mg) at the 12-week visit, 2.5 mg QD will be restarted if the LVEF is ≥ 50%.

[0592] If the dose is increased (including from 0 mg to 2.5 mg QD), patients will return to the clinic 4 weeks after the dose increase to assess LVEF. Patients will continue on the same dose for the next 8 weeks unless LVEF is <50%. Beginning at Week 12, patients will have clinic visits every 12 weeks during which LVEF and VLVOT will be determined, and the dose may be increased by one level if LVEF is ≥55% and VLVOT ≥30 mmHg. The maximum dose of mavacet is 15 mg QD. If LVEF is <50% twice at 2.5 mg QD during treatment, permanently discontinue treatment.

[0593] Concomitant administration of mavaketide with moderate and strong inhibitors of CYP2C19 is contraindicated. Concomitant administration of mavaketide with strong inhibitors of CYP3A4 is contraindicated. Concomitant administration of mavaketide with moderate and strong inducers of CYP3A4 or CYP2C19 is contraindicated.

[0594] Mavaketal capsules for oral use

[0595] WARNING: Risk of heart failure

[0596] · Mavaketide may cause heart failure due to systolic dysfunction.

[0597] An echocardiographic assessment of left ventricular ejection fraction (LVEF) is required prior to and during use of Mavaketal.

[0598] Not recommended for initiation in patients with LVEF < 55%. Discontinue if LVEF < 50% or if clinical condition worsens.

[0599] Certain CYP450 inducers are contraindicated in patients taking mavacet because of an increased risk of heart failure.

[0600] Malvacetta is available only through a restricted program called the Malvacetta REMS Program.

[0601] Indications and Usage

[0602] Mavacet is a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

[0603] Dosage and Administration

[0604] The dose must be individualized based on clinical status and echocardiographic assessment of the patient's response. Please refer to the full prescribing information for instructions.

[0605] Dosage forms and strengths

[0606] Capsules: 2.5 mg, 5 mg, 10 mg and 15 mg

[0607] Contraindications

[0608] Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors

[0609] Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers

[0610] Warnings and Precautions

[0611] Heart failure: Consider interruption of Mavaketamine in patients with concurrent medical conditions.

[0612] Drug interactions leading to heart failure or loss of effectiveness: Inform patients of the potential for drug interactions, including interactions with over-the-counter medications.

[0613] Embryo-Fetal Toxicity: May cause fetal harm. Inform females of reproductive potential to use effective contraception for 4 months after the last dose. Use a contraceptive that is not affected by CYP 450 enzyme induction or add a non-hormonal contraceptive.

[0614] Adverse Reactions

[0615] Adverse reactions occurring in >5% of patients and more commonly in patients taking mavaketide than in those taking placebo were dizziness (27%) and syncope (6%).

[0616] Drug interactions

[0617] Weak CYP2C19 and moderate CYP3A4 inhibitors: May increase the risk of heart failure. If an inhibitor is initiated, a reduction in the mavaketide dose and additional monitoring may be required.

[0618] Negative inotropes: Close medical supervision and LVEF monitoring are recommended if initiating or increasing the dose of negative inotropes. Avoid certain combinations of negative inotropes.

[0619] Full Prescribing Information

[0620] WARNING: Risk of heart failure

[0621] Malvaketamine can reduce left ventricular ejection fraction (LVEF) and may lead to heart failure due to systolic dysfunction.

[0622] Echocardiographic assessment of LVEF is required prior to and during treatment with mavaketela. Initiation of mavaketela is not recommended in patients with LVEF <55%. Interrupt mavaketela if LVEF is <50% at any visit or if the patient experiences symptoms of heart failure or worsening clinical status.

[0623] Concomitant use of mavaketide with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, concomitant use of mavaketide with the following is contraindicated:

[0624] Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors

[0625] Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers

[0626] Because of the risk of heart failure due to systolic dysfunction, Mavaketal is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Mavaketal REMS Program.

[0627] 1. Indications and Usage

[0628] Mavaketal is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

[0629] 2. Dosage and Administration

[0630] 2.1. Initiation, maintenance and discontinuation of treatment

[0631] Confirm that females of childbearing potential are not pregnant and are using effective contraception.

[0632] Initiation or up-titration of mavaketide is not recommended in patients with LVEF <55%.

[0633] The recommended starting dose is 5 mg once daily, regardless of food; subsequent doses permitted after titration are 2.5 mg, 5 mg, 10 mg, or 15 mg once daily.

[0634] Patients may develop heart failure while taking Mavaketide. Regular LVEF and Valsalva left ventricular outflow tract (LVOT) gradient assessments are required to allow careful titration to achieve an appropriate target Valsalva LVOT gradient while maintaining an LVEF ≥ 50% and avoiding symptoms of heart failure (see Figure 4 and Figure 5 ).

[0635] Daily dosing requires weeks to achieve steady-state drug levels and therapeutic effects, and genetic variation in metabolism and drug interactions can lead to large differences in exposure.

[0636] When initiating or titrating mavaketal, consider LVEF first, then the Valsalva LVOT gradient and the patient's clinical status to guide appropriate mavaketal dosing. Figure 4 ) and maintain ( Figure 5 ) algorithm to obtain an appropriate mavaketal dosing and monitoring plan.

[0637] If LVEF < 50% while taking Mavaketide, interrupt treatment. Figure 6 ) algorithm to guide interruption, restart, or discontinuation of Mavaketal. If interrupted at 2.5 mg, restart at 2.5 mg or permanently discontinue.

[0638] Figure 4 The starting phase is shown. Figure 5 The maintenance phase is shown. Figure 6 showed that treatment was discontinued at any clinic visit if LVEF <50%.

[0639] Delay dose escalation when concurrent illness (e.g., severe infection) or arrhythmias (e.g., atrial fibrillation or other uncontrolled tachycardia) that may impair contractile function are present. Consider interruption of Mavaketide in patients with concurrent illness.

[0640] Missed or delayed dose

[0641] If a dose is missed, it should be taken as soon as possible and the next scheduled dose should be taken at the regular time the next day. The exact time of day the dose is taken is not important, but two doses should not be taken on the same day.

[0642] Swallow the capsule whole. Do not break, open, or chew the capsule.

[0643] 2.2. Concomitant Administration of Weak CYP2C19 or Moderate CYP3A4 Inhibitors

[0644] Initiate mavacetir at the recommended starting dose of 5 mg orally once daily in patients receiving stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor.

[0645] In patients initiating a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, reduce the dose of mavaketide by one level (i.e., from 15 mg to 10 mg, from 10 mg to 5 mg, or from 5 mg to 2.5 mg). Schedule clinical and echocardiographic evaluations 4 weeks after inhibitor initiation, and do not titrate mavaketide within 12 weeks after inhibitor initiation. Avoid initiation of concomitant use of weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are receiving stable treatment with 2.5 mg mavaketide, as there is no lower mavaketide once-daily dose.

[0646] 3. Dosage form and specifications

[0647] Mavaket is available in capsule form with the following strengths and "Mava" printed on it:

[0648] 2.5mg – Light purple cap

[0649] 5mg – Yellow bottle cap

[0650] 10mg – pink bottle cap

[0651] 15mg – Grey cap

[0652] 4. Contraindications

[0653] Concomitant use of Mavaketal with the following drugs is contraindicated:

[0654] Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors

[0655] Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers

[0656] 5. Warnings and Precautions

[0657] Heart failure

[0658] Malvacetide decreases systolic contractility and may lead to heart failure or complete blockade of ventricular function. Patients experiencing severe concurrent illness (e.g., severe infection) or cardiac arrhythmias (e.g., atrial fibrillation or other uncontrolled tachycardia) are at greater risk for systolic dysfunction and heart failure.

[0659] Assess the patient's clinical status and LVEF prior to and periodically during treatment and adjust the mavaketide dose accordingly. New or worsening arrhythmias, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function.

[0660] Asymptomatic reductions in LVEF, intercurrent illness, and arrhythmias require additional dosing considerations.

[0661] Initiation of mavaketal in patients with LVEF <55% is not recommended. Avoid concomitant use of mavaketal in patients taking disopyramide, ranolazine, verapamil with beta-blockers, or diltiazem with beta-blockers, as these drugs and combinations were excluded from the clinical study of mavaketal in obstructive HCM (EXPLORER-HCM). Concomitant use of mavaketal with disopyramide in combination with verapamil or diltiazem has been associated with left ventricular systolic dysfunction and symptoms of heart failure in patients with obstructive HCM.

[0662] 5.2. CYP 450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness

[0663] Mavaketide is primarily metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant use of mavaketide and drugs that interact with these enzymes may result in life-threatening drug interactions, such as heart failure or loss of effectiveness.

[0664] Inform patients of the potential for drug interactions, including interactions with over-the-counter medications such as omeprazole, esomeprazole, or cimetidine. Inform patients to tell their healthcare provider about all concomitant products before and during treatment with Mavaketel.

[0665] 5.3. Mavaketal REMS Program

[0666] Because of the risk of heart failure due to systolic dysfunction, Malvaketal is available only through a restricted program called the Malvaketal REMS Program.

[0667] Notable requirements of the Mavaketal REMS program include the following:

[0668] Prescribers must be certified by enrolling in the Mavaketal REMS program.

[0669] Patients must be enrolled in the Mavaketal REMS program and comply with ongoing monitoring requirements.

[0670] Pharmacies must be certified by enrolling in the Malvaketal REMS program and must only dispense Malvaketal to patients authorized to receive it.

[0671] Wholesalers and distributors must distribute only to certified pharmacies.

[0672] 5.4. Embryo-fetal toxicity

[0673] Based on findings from animal studies, mavaketide may cause fetal toxicity when administered to pregnant females. Confirm that females of reproductive potential are not pregnant prior to treatment and inform patients to use effective contraception during treatment with mavaketide and for 4 months after the last dose. Mavaketide may reduce the effectiveness of combined hormonal contraceptives (CHCs). Inform patients taking CHCs to use an alternative method of contraception that is not affected by CYP 450 enzyme induction or to add non-hormonal contraception.

[0674] Inform females of reproductive potential of the potential risk to the fetus from maternal exposure to malvacetide during pregnancy.

[0675] 6. Adverse Reactions

[0676] The following adverse reactions are discussed in other subsections of the labeling:

[0677] Heart failure

[0678] 6.1 Clinical Trial Experience

[0679] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

[0680] The safety of mavaketal was evaluated in EXPLORER-HCM, a Phase 3 double-blind, randomized, placebo-controlled trial. Among 251 adults with obstructive HCM, 123 patients were treated with mavaketal 2.5-15 mg daily and 128 patients were treated with placebo. The median exposure duration for mavaketal-treated patients was 30 weeks (range: 2-40 weeks).

[0681] Syncope (0.8%) was the only adverse drug reaction leading to discontinuation in patients receiving mavaketamine.

[0682] Adverse reactions occurring in >5% of patients and more commonly in patients taking mavaketide than in patients taking placebo were dizziness (27% vs. 18%) and syncope (6% vs. 2%).

[0683] Effects on contractile function

[0684] In the EXPLORER-HCM trial, the mean (SD) resting LVEF at baseline was 74% in both treatment groups (6). Consistent with the mechanism of action of mavaketal, the mean (SD) absolute change from baseline in LVEF over the 30-week treatment period was -4% in the mavaketal group (8) and 0% in the placebo group (7). At Week 38, 8 weeks after interruption of study drug, mean LVEF was similar to baseline in both treatment groups. In the EXPLORER-HCM trial, 7 patients (6%) in the mavaketal group and 2 patients (2%) in the placebo group experienced a reversible decrease in LVEF to <50% (median 48%: range 35-49%) during treatment. These decreases were asymptomatic in 3 of the 7 mavaketal patients and 1 of the 2 placebo patients. In all 7 patients treated with mavaketal, LVEF recovered after interruption of mavaketal treatment.

[0685] 7. Drug Interactions

[0686] 7.1. Potential of Other Drugs Affecting Plasma Concentrations of Mavaketal

[0687] Mavaketide is primarily metabolized by CYP2C19 and, to a lesser extent, by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposure of Mavaketide. (See Table 1)

[0688] Table 1: Identified and potentially significant pharmacokinetic drug interactions with Mavaketal

[0689] Effects of other drugs on Mavaket

[0690]

[0691]

[0692] 7.2. Potential of Mavaketide to Affect Plasma Concentrations of Other Drugs

[0693] Mavaketide is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may decrease the plasma concentrations of these drugs. When mavaketide is used in combination with CYP3A4, CYP2C19, or CYP2C9 substrates, close monitoring should be performed for decreased plasma concentrations of these drugs that may reduce their activity.

[0694] Hormonal Contraceptives: Progestins and ethinyl estradiol are CYP3A4 substrates. Concomitant use of mavaketide may decrease the exposure of ethinyl estradiol and progestins, which could lead to contraceptive failure or increased breakthrough bleeding. Inform patients to use a contraceptive method that is not affected by CYP 450 enzyme induction (e.g., an intrauterine system) or add a non-hormonal contraceptive method (such as condoms) during concomitant use and for 4 months after the last mavaketide dose.

[0695] 7.3. Drugs that reduce cardiac contractility

[0696] Additive negative inotropic effects are expected with mavaketide and other drugs that reduce cardiac contractility. In the EXPLORER-HCM trial, of the 123 patients receiving mavaketide, 119 received concomitant therapy with beta-blockers (n=94), verapamil (n=19), or diltiazem (n=6).

[0697] Avoid concomitant use of mavaketil with disopyramide in combination with verapamil or diltiazem as such use has been associated with left ventricular systolic dysfunction and symptoms of heart failure.

[0698] If concomitant therapy with a negative inotropic agent is initiated, or if the dose of a negative inotropic agent is increased, monitor LVEF closely until a stable dose and clinical response is achieved.

[0699] 8. Use in Specific Populations

[0700] 8.1. Pregnancy

[0701] Risk Overview

[0702] Based on animal data, mavaketal may cause fetal harm when administered to a pregnant female. There are no human data on the use of mavaketal during pregnancy to assess the drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Underlying maternal conditions during pregnancy pose risks to both the mother and the fetus. Inform females of reproductive potential that maternal exposure to mavaketal during pregnancy may cause potential risks to the fetus.

[0703] In animal embryo-fetal development studies, at doses similar to those achieved at the maximum recommended human dose (MRHD), mavacetal-associated decreases in mean fetal body weights, reduced fetal skeletal ossification, and increased post-implantation losses (early and / or late resorptions) were observed in rats, and increased visceral and skeletal malformations were observed in both rabbits and rats.

[0704] The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies carry a risk of birth defects, death, or other adverse outcomes. In the general U.S. population, the estimated background risks of major birth defects and miscarriage in clinically diagnosed pregnancies are 2% to 4% and 15% to 20%, respectively.

[0705] There is a pregnancy safety study for mavaketal. Healthcare providers should report mavaketal exposure if mavaketal is administered during pregnancy or if a patient becomes pregnant while receiving mavaketal or within 4 months after the last dose of mavaketal.

[0706] Clinical considerations

[0707] Disease-Associated Maternal and Embryo-Fetal Risks

[0708] Obstructive HCM during pregnancy is associated with an increased risk of preterm birth.

[0709] data

[0710] Animal data

[0711] When mavaketide (0.3 to 1.5 mg / kg / day) was orally administered to pregnant rats during the period of organogenesis, an increase in postimplantation mortality, decreased mean fetal weights, decreased fetal skeletal ossification, and fetal malformations (visceral and skeletal) were observed in the high-dose group (1.5 mg / kg / day). An increase in the incidence of visceral malformations (fetal cardiac malformations, including one case of complete situs inversus) and skeletal malformations (primarily sternal fusion) was observed at exposures similar to the MRHD in humans. The plasma exposure (based on the area under the concentration-time curve or AUC) at the no-effect dose on embryo-fetal development in rats was 0.3 times the human MRHD exposure.

[0712] During the period of organogenesis, when mavacetide (0.6 to 2.0 mg / kg / day) was administered orally to pregnant rabbits, fetal malformations (visceral and skeletal) were increased at doses of 1.2 mg / kg / day and above, with plasma exposures similar to the human MRHD at 1.2 mg / kg / day. Visceral findings consisted of large vessel malformations (dilatation of the pulmonary trunk and / or aortic arch). Skeletal malformations consisted of a higher incidence of sternal fusions at ≥1.2 mg / kg / day. Plasma exposures (AUC) in rabbits at the no-effect-on-embryo-fetal development dose were 0.4 times the human MRHD.

[0713] In a prenatal / postnatal development study, mavacetide (0.3 to 1.5 mg / kg / day) was orally administered to pregnant rats from gestational day 6 to lactation / postnatal day 20. No adverse effects were observed in dams and offspring exposed daily from prenatal (in utero) through lactation. The no observed adverse effect level (NOAEL) was 1.5 mg / kg / day (the highest dose level tested), which resulted in exposures (AUC) similar to those at the human MRHD.

[0714] 8.2. Breastfeeding

[0715] Risk Overview

[0716] It is unknown whether malvacetate is present in human or animal milk, the effects of the drug on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered, as should the mother's clinical need for malvacetate and any potential adverse effects on the breastfed infant from malvacetate or the underlying maternal condition.

[0717] 8.3. Females and males of childbearing potential

[0718] Based on animal data, mavacetel may cause fetal harm when administered to a pregnant female.

[0719] Pregnancy test

[0720] Before starting Mavaketamine, confirm that females of childbearing potential are not pregnant.

[0721] Contraception

[0722] female

[0723] Inform females of reproductive potential to use effective contraception during treatment with mavaketal and for 4 months after the last dose. Use of mavaketal may reduce the effectiveness of CHCs. Inform patients taking CHCs to use an alternative method of contraception or add non-hormonal contraception.

[0724] 8.4. Pediatric Use

[0725] The safety and effectiveness of mavacetal in pediatric patients have not been established.

[0726] 8.5. Use by the Elderly

[0727] Clinical trials included 263 patients dosed with mavacet, of whom 95 patients were aged 65 years or older (36.1%) and 17 patients (6.5%) were aged 75 years or older. Safety, efficacy, and pharmacokinetics were similar between patients ≥65 years and younger patients.

[0728] 8.6. Liver Damage

[0729] No dose adjustment is required in patients with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment. Mavaketide exposure (AUC) was increased by up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function. However, for patients with mild to moderate hepatic impairment, following the recommended dose titration algorithm and monitoring schedule, no additional dose adjustment is required. The effect of severe (Child-Pugh C) hepatic impairment is unknown.

[0730] 10. Overdose

[0731] There is limited human experience with overdose of malvacetide. In patients with HCM, malvacetide has been given as a single dose up to 144 mg. One subject administered a single dose of 144 mg experienced serious adverse events, including vasovagal reactions, hypotension, and cardiac arrest, but the subject recovered. In healthy subjects, doses up to 25 mg have been administered for up to 25 days, with 3 of 8 participants treated with the 25 mg dose level experiencing a decrease in LVEF of 20% or more. Death has been reported in an infant following accidental ingestion of three 15 mg capsules.

[0732] Systolic dysfunction is the most likely consequence of an overdose of malvaketal. Treatment of an overdose of malvaketal includes discontinuation of malvaketal therapy and medical supportive measures to maintain hemodynamic stability, including close monitoring of vital signs and LVEF and management of the patient's clinical condition. Overdose in humans may be life-threatening and result in cardiac arrest refractory to any medical intervention.

[0733] 11. Description

[0734] Mavaketal capsules for oral use contain mavaketal, a cardiac myosin inhibitor.

[0735] The chemical name of Mavaketyl is 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]-2,4(1H,3H)-pyrimidinedione. The molecular formula is C 15 H 19 N3O2, and the molecular weight is 273.33 g / mol.

[0736] The structural formula of Mavaketye is:

[0737]

[0738] Mavaketyl is a white to off-white powder that is practically insoluble in water and aqueous buffers at pH 2-10, slightly soluble in methanol and ethanol, and freely soluble in DMSO and NMP.

[0739] Mavaketal is supplied in size 2 immediate-release hard gelatin capsules, each containing 2.5 mg, 5 mg, 10 mg or 15 mg of Mavaketal as the active ingredient, and the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate (non-bovine), mannitol and silicon dioxide. The capsule shell contains black edible ink, black iron oxide, gelatin, red iron oxide, titanium dioxide and yellow iron oxide.

[0740] 12. Clinical Pharmacology

[0741] 12.1. Mechanism of action

[0742] Marvacet is an allosteric, reversible inhibitor that is selective for cardiac myosin. Marvacet modulates the number of myosin heads that can enter the "on actin" (power-generating) state, thereby reducing the probability of force-generating (systolic) and residual (diastolic) cross-bridge formation. Excessive myosin-actin cross-bridge formation and dysregulation of the hyper-relaxed state are mechanistic hallmarks of HCM. Marvacet shifts the global myosin population toward an energy-efficient, recruitable, hyper-relaxed state. In patients with HCM, myosin inhibition with Marvacet reduces dynamic LVOT obstruction and improves cardiac filling pressures.

[0743] 12.2. Pharmacodynamics

[0744] Left ventricular ejection fraction and left ventricular outflow tract obstruction

[0745] In the EXPLORER-HCM trial, patients achieved reductions in mean resting and evoked (Valsalva) LVOT gradients by week 4, and this effect was maintained throughout the 30-week trial. At week 30, the mean (SD) changes from baseline in resting and Valsalva LVOT gradients were -39 (29) mmHg and -49 (34) mmHg, respectively, for the mavaketal group and -6 (28) mmHg and -12 (31) mmHg, respectively, for the placebo group. The reduction in Valsalva LVOT gradient was accompanied by a decrease in LVEF, which was generally within normal limits. Eight weeks after stopping mavaketal, mean LVEF and Valsalva LVOT gradient were similar to baseline.

[0746] Heart structure

[0747] In EXPLORER-HCM, echocardiographic measurements of cardiac structure showed a mean (SD) decrease in left ventricular mass index (LVMI) from baseline in the mavaketal group at week 30 (-7.4 [17.8] g / m 2 ), while the LVMI in the placebo group increased (8.9 [15.3] g / m 2 The left atrial volume index (LAVI) in the Mavaketide group also decreased by a mean (SD) from baseline (-7.5 [7.8] mL / m 2 ), while there was no change in the placebo group (-0.1[8.7]mL / m 2 ). The clinical significance of these findings is unclear.

[0748] Cardiac biomarkers

[0749] In the EXPLORER-HCM trial, reductions in the cardiac wall stress biomarker NT-proBNP were observed by week 4 and were sustained until the end of treatment. The reduction in NT-proBNP from baseline at week 30 was 80% greater with mavacetib than with placebo (geometric mean odds ratio between the two groups, 0.20 [95% CI: 0.17, 0.24]). The clinical significance of these findings is unclear.

[0750] Cardiac Electrophysiology

[0751] In healthy volunteers receiving multiple doses of mavacet, concentration-dependent increases in the QTc interval were observed at doses up to 25 mg once daily. During single-dose studies, no acute QTc changes were observed at similar exposures. The mechanism of the QT prolonging effect is unknown.

[0752] Meta-analyses of clinical studies in patients with HCM did not demonstrate a clinically relevant increase in the QTc interval over the therapeutic exposure range. In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, association with ventricular pacing, or association with medications commonly used in the HCM population that may cause QT prolongation. The effects of coadministration of mavaketide with QT prolonging medications or in patients with potassium channel variants that prolong the QT interval have not been characterized.

[0753] 12.3. Pharmacokinetics

[0754] Following multiple once-daily doses of 1 mg to 15 mg, mavacetuximab exposure generally increased in a dose-proportional manner. At the same mavacetuximab dose level, 170% higher mavacetuximab exposure was observed in HCM patients compared to healthy subjects.

[0755] absorb

[0756] The estimated oral bioavailability of Mavaketel is at least 85% and the time of maximum concentration (Tmax) is 1 hour.

[0757] Effects of food

[0758] No clinically significant differences in the pharmacokinetics of mavacetide were observed following administration with a high-fat meal. Tmax was increased by 4 hours.

[0759] distributed

[0760] The plasma protein binding rate of Mavaketal is between 97% and 98%.

[0761] eliminate

[0762] Mavaketide has a variable terminal t1 / 2, which depends on the CYP2C19 metabolic state. In CYP2C19 normal metabolizers (NM), the terminal half-life of Mavaketide is 6-9 days, which is extended to 23 days in CYP2C19 poor metabolizers (PM). In CYP2C19 NM, drug accumulation occurs at an accumulation rate of about 2 times for Cmax and about 7 times for AUC. Accumulation depends on the metabolic state of CYP2C19, with the greatest accumulation observed in CYP2C19 PM. At steady state, the peak-to-trough plasma concentration ratio for once-daily dosing is about 1.5.

[0763] metabolism

[0764] Mavaketide is extensively metabolized primarily by CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%).

[0765] excretion

[0766] Following a single 25 mg dose of radiolabeled mavacetir, 7% of the dose was recovered in feces (1% unchanged) and 85% was recovered in urine (3% unchanged).

[0767] Specific population

[0768] The differences were not statistically significant among age (range: 18-82 years), sex, race, ethnicity, or mild (eGFR: 60 to 89 mL / min / 1.73 m 2 ) to moderate (eGFR: 30 to 59 mL / min / 1.73 m 2 ) Renal impairment: No clinically significant differences in the pharmacokinetics of mavaketide were observed. Severe renal impairment (eGFR: 15 to 30 mL / min / 1.73 m 2 ) and renal failure (eGFR: <15mL / min / 1.73m 2 ; including patients receiving dialysis) is unclear.

[0769] Liver damage

[0770] In patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, mavacetir exposure (AUC) was increased by up to 220%. The effect of severe (Child-Pugh C) hepatic impairment is unknown.

[0771] Drug interactions

[0772] Clinical research and model-guided approaches

[0773] Weak CYP2C19 Inhibitors: Concomitant use of mavaketide (15 mg) and omeprazole (20 mg) once daily increased mavaketide AUCinf by 48% but had no effect on Cmax in healthy CYP2C19 NMs and rapid metabolizers (RMs; e.g. *1 / *17).

[0774] Moderate CYP3A4 Inhibitors: Concomitant use of mavaketal (25 mg) with extended-release verapamil (240 mg) increased mavaketal AUCinf by 15% and Cmax by 52% in moderate metabolizers (IM; e.g., *1 / *2, *1 / *3, *2 / *17, *3 / *17) and NMs of CYP2C19. Concomitant use of mavaketal with diltiazem in CYP2C19 PMs is predicted to increase mavaketal AUC0-24h and Cmax by up to 55% and 42%, respectively.

[0775] Strong CYP3A4 Inhibitors: Concomitant use of mavaketide (15 mg) with ketoconazole 400 mg once daily is expected to increase mavaketide AUC0-24 and Cmax by up to 130% and 90%, respectively.

[0776] Strong CYP2C19 and CYP3A4 Inducers: Concomitant use of mavacetel (single dose 15 mg) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily) is expected to decrease mavacetel AUC0-inf and Cmax by 87% and 22%, respectively, in CYP2C19 NM and by 69% and 4%, respectively, in CYP2C19 PM.

[0777] CYP3A4 Substrates: In healthy CYP2C19 NM, concomitant use of a 16-day course of mavaketide (25 mg on days 1 and 2, then 15 mg for 14 days) resulted in a 13% and 7% decrease in midazolam AUCinf and Cmax, respectively. Once-daily co-administration of mavaketide in HCM patients is expected to reduce midazolam AUCinf and Cmax by 21% to 64% and 13% to 48%, respectively, depending on the mavaketide dose and CYP2C19 phenotype.

[0778] CYP2C8 Substrates: Concomitant use of mavaketide once daily in HCM patients is expected to decrease the AUC and Cmax of repaglinide (CYP2C8 and CYP3A substrate) by 12% to 39%, depending on the mavaketide dose and CYP2C19 phenotype.

[0779] CYP2C9 Substrates: Concomitant use of mavaketide once daily in HCM patients is expected to decrease the AUC and Cmax of tolbutamide (CYP2C9 substrate) by 33% to 65%, depending on the mavaketide dose and CYP2C19 phenotype.

[0780] CYP2C19 Substrates: Concomitant use of mavaketide once daily in HCM patients is expected to decrease the AUC and Cmax of omeprazole (CYP2C19 substrate) by 48% to 67%, depending on the mavaketide dose and CYP2C19 phenotype.

[0781] In vitro studies

[0782] CYP Enzymes: Mavaketide does not inhibit CYP1A2, CYP2B6, or CYP2C8. At clinically relevant concentrations, Mavaketide is not an inhibitor of CYP2D6, CYP2C9, CYP2C19, or CYP3A4. Mavaketide is a CYP2B6 inducer.

[0783] Transport Systems: Mavaketide does not inhibit P-gp, BCRP, BSEP, MATE1, MATE2-K, organic anion transporting polypeptide (OATP), organic cation transporter (OCT), or organic anion transporter (OAT).

[0784] 12.5 Pharmacogenomics

[0785] After a single 15 mg dose of mavaketide, the AUCinf of mavaketide in CYP2C19 poor metabolizers (PMs) was increased by 241% and the Cmax was increased by 47% compared to normal metabolizers (NMs). The mean half-life was prolonged in CYP2C19 PMs compared to NMs (23 days and 6 to 9 days, respectively).

[0786] Polymorphic CYP2C19 is the main enzyme involved in the metabolism of mavaketide. Individuals carrying two normal functional alleles are NM (e.g., *1 / *1). Individuals carrying two non-functional alleles are PM (e.g., *2 / *2, *2 / *3, *3 / *3).

[0787] The prevalence of CYP2C19 poor metabolizers varies by ancestry. Approximately 2% of individuals of European ancestry and 4% of individuals of African ancestry are PMs; the prevalence of PMs is higher in Asian populations (e.g., approximately 13% of East Asians).

[0788] 13. Nonclinical toxicology

[0789] 13.1. Carcinogenesis, Mutagenesis and Impairment of Fertility

[0790] Mavaketel was not genotoxic in the bacterial reverse mutation test (Ames test), the human in vitro lymphocyte clastogenicity assay, or the in vivo rat micronucleus assay.

[0791] In a 6-month study in rasH2 transgenic mice, no evidence of carcinogenicity was observed at doses of mavaketide up to 2.0 mg / kg / day in male mice and 3.0 mg / kg / day in female mice (these doses resulted in 1.8-fold and 3-fold exposures (AUC) in males and females, respectively, compared to the AUC exposure at the human MRHD).

[0792] In reproductive toxicity studies, there was no evidence that mavaketide had an effect on mating or fertility in male or female rats at doses up to 1.2 mg / kg / day, nor was there any evidence that mavaketide had an effect on offspring viability or fertility in female rats at doses up to 1.5 mg / kg / day. Plasma exposure (AUC) of mavaketide at the highest dose tested was equivalent to the human MRHD.

[0793] 13.2. Animal Toxicology and / or Pharmacology

[0794] The safety of mavaketide has been evaluated orally in rats and dogs at multiple dose levels (0.06 to 10 mg / kg / day). Toxicity noted included echocardiographic findings, decreased systolic function, cardiac dilatation and death, and increased cardiac weight in rats, which are consistent with the mechanism of action and primary pharmacological activity of mavaketide. Other findings included cardiac bone metaplasia in rats and QTc prolongation in dogs. Plasma NOAEL exposures (AUC) in rats and dogs were 0.1 and 0.3 times the human MRHD exposures (AUC), respectively.

[0795] 14. Clinical research

[0796] Obstructive hypertrophic cardiomyopathy

[0797] The efficacy of mavaketal was evaluated in EXPLORER-HCM (NCT-03470545), a phase 3, double-blind, randomized, placebo-controlled, multicenter, international, parallel-group trial in 251 adults with symptomatic NYHA class II and III obstructive HCM, LVEF ≥55%, and Valsalva LVOT peak gradient ≥50 mmHg at rest or provocation.

[0798] Patients receiving dual therapy with a beta-blocker and a calcium channel blocker or monotherapy with disopyramide or ranolazine were excluded. Patients with known infiltrative or storage disorders that cause cardiac hypertrophy similar to obstructive HCM (such as Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy) were also excluded.

[0799] Patients were randomized in a 1:1 ratio to receive either mavacetal at a starting dose of 5 mg or placebo once daily for 30 weeks. Treatment assignment was stratified according to baseline NYHA functional class, baseline beta-blocker use, and ergometer type (treadmill or exercise bike).

[0800] The groups had different age (average 59 years), BMI (average 30 kg / m 2 The participants were well matched for 100 mg / dL, 100 mg / dL, 200 mg / dL of levofloxacin, 100 mg / dL of nab-1a, 100 mg / dL of dL of lipoprotein (MPa), heart rate (mean 62 bpm), blood pressure (mean 128 / 76 mmHg), and race (90% Caucasian). Fifty-four percent of the participants in the mavaket

[0801] At baseline, approximately 73% of randomized patients were in NYHA class II and 27% were in NYHA class III. The mean LVEF was 74%, and the mean Valsalva LVOT gradient was 73 mmHg. Approximately 10% of patients had received prior septal volume reduction therapy, 75% were receiving beta-blockers, 17% were receiving calcium channel blockers, and 14% had a history of atrial fibrillation.

[0802] All patients were started on 5 mg mavaketide (or matching placebo) once daily, and the dose was adjusted regularly to optimize patient response (reduction of LVOT gradient by Valsalva maneuver) and maintain LVEF ≥ 50%. The dose was also determined based on mavaketide plasma concentrations.

[0803] In the mavaketal group, at the end of treatment, 49% of patients were receiving the 5 mg dose, 33% were receiving the 10 mg dose, and 11% were receiving the 15 mg dose. Three patients temporarily stopped their dose due to LVEF <50%, of which two were resumed at the same dose and one had the dose reduced from 10 mg to 5 mg.

[0804] Primary End Point

[0805] The primary composite functional endpoint assessed at 30 weeks was defined as the proportion of patients achieving an improvement in mixed venous oxygen tension (pVO2) of ≥1.5 mL / kg / min with an improvement in NYHA class of at least 1 grade or an improvement in pVO2 of ≥3.0 mL / kg / min with no worsening of NYHA class.

[0806] A greater proportion of patients in the mavaketide group achieved the primary endpoint at Week 30 compared with the placebo group (37% vs. 17%, respectively, p=0.0005; see Table 2).

[0807] Table 2: Primary endpoints at 30 weeks

[0808]

[0809] The effects of a range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications on the outcomes were examined. The results of the primary analysis consistently supported the efficacy of mavaketide in all analyzed subgroups. Fig.17 ).

[0810] Fig.17 Subgroup analyses of the primary composite functional endpoint are shown.

[0811] The dashed vertical line represents the overall treatment effect, and the solid vertical line (no effect) indicates no difference between treatment groups. Note: The figure shows the effect in each subgroup, all baseline characteristics. The 95% confidence limits shown do not take into account the number of comparisons made and may not reflect the effect of a specific factor after adjusting for all other factors. Apparent homogeneity or heterogeneity between groups should not be over-interpreted.

[0812] Although the benefit of mavaketide was smaller (attenuated improvement in pVO2) in patients receiving background beta-blocker therapy compared with those not receiving background beta-blocker therapy, analyses of other secondary endpoints (symptoms, LVOT gradient) suggest that patients may benefit from mavaketide treatment regardless of beta-blocker use.

[0813] Secondary End Points

[0814] The treatment effects of mavaketide on LVOT obstruction, functional capacity, and health status were assessed by changes in peak LVOT gradient after exercise, changes in pVO2, proportion of patients with improvement in NYHA class, Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) Clinical Summary Score (CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) Shortness of Breath (SoB) domain score from baseline to week 30. At week 30, patients receiving mavaketide had significantly greater improvements in all secondary endpoints compared with those receiving placebo (Table 3, Table 3). Fig.18 , Fig.19 , Table 4 and Figure 7-10 ).

[0815] Table 3: Changes in LVOT gradient, pVO2, and NYHA class after exercise from baseline to week 30

[0816]

[0817] Fig.18 Cumulative distribution of change in LVOT peak gradient from baseline to week 30 is shown

[0818] Fig.19 Cumulative distribution of change in pVO2 from baseline to week 30 is shown

[0819] Table 4: Changes from Baseline to Week 30 in KCCQ-23CSS and HCMSQ SoB Domains

[0820]

[0821] The KCCQ-23 CSS is derived from the Total Symptom Score (TSS) and Physical Limitation (PL) score of the KCCQ-23. The CSS ranges from 0 to 100, with higher scores indicating less severe symptoms and / or physical limitations.

[0822] The HCMSQ SoB domain score measures the frequency and severity of shortness of breath. The HCMSQ SoB domain score ranges from 0 to 18, with lower scores indicating less severe shortness of breath.

[0823] Missing data were not imputed to summarize baseline and change from baseline to Week 30. Repeated measures mixed models were used to assess differences in mean changes from baseline between treatment groups.

[0824] Figure 7 The time course of KCCQ-23CSS changes is shown. Figure 8 The distribution of the change in KCCQ-23CSS from baseline to Week 30 is shown.

[0825] The graph shows the cumulative percentage of patients who achieved a certain level of response.

[0826] Fig. 9 The time course of changes in HCMSQ SoB is shown. Fig.10 The distribution of the change from baseline to week 30 in HCMSQ SoB is shown.

[0827] 16. How to supply / storage and handling

[0828] Mavaketal is supplied as size 2 immediate-release hard gelatin capsules containing 2.5 mg, 5 mg, 10 mg, or 15 mg of Mavaketal. The white opaque capsule body is printed with "Mava" and the strength is printed on the opaque cap. The capsule contains a white to off-white powder. Mavaketal capsules are supplied in bottles of 30 capsules as listed in the table below:

[0829] Specification Capsule cover NDC Number 2.5mg Light Purple 73625-111-11 5mg yellow 73625-112-11 10mg pink 73625-113-11 15mg grey 73625-114-11

[0830] store

[0831] Store at 20°C to 25°C (68°F to 77°F), with fluctuations permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

[0832] 17. Patient Counseling Information

[0833] Inform patients and / or caregivers to read the FDA-approved patient labeling (Medication Guide).

[0834] Heart failure

[0835] Inform patients that cardiac function monitoring using echocardiography is necessary to monitor for heart failure. Inform patients to report any signs or symptoms of heart failure immediately to their healthcare provider.

[0836] Drug interactions

[0837] Inform patients to tell their healthcare provider about all concomitant products, including over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine) and supplements before and during treatment with mavacetal.

[0838] Mavaketal REMS Program

[0839] Malvaketal is available only through a restricted program called the Malvaketal REMS Program. Inform patients of these important requirements:

[0840] Patients must be enrolled in the program and comply with ongoing monitoring requirements.

[0841] Malvaketal is prescribed only by certified healthcare providers and dispensed only by certified pharmacies participating in the program. Patients are provided with a phone number and website for information on how to obtain the product.

[0842] Embryo-fetal toxicity

[0843] Inform pregnant women and females of reproductive potential of the potential risk to a fetus. Inform females of reproductive potential to tell their healthcare provider of a known or suspected pregnancy.

[0844] Inform females of reproductive potential to use effective contraception during treatment with mavaketamine and for 4 months after the last dose. Inform patients taking CHCs to use an alternative method of contraception or add non-hormonal contraception because mavaketamine may reduce the efficacy of CHCs.

[0845] Inform women exposed to mavaketamine during pregnancy of the existence of pregnancy safety studies monitoring pregnancy outcomes.

[0846] Instructions for taking Mavaketal

[0847] Mavaketal capsules should be swallowed whole. Inform patients that if they miss a dose of Mavaketal, they should take that dose as soon as possible that day and take the next scheduled dose at the regular time the next day. Patients should not take two doses on the same day.

[0848] Example 2. Simulation of Dosing Regimens for Safety and Efficacy

[0849] Mavaketel has considerable pharmacokinetic (PK) variability, with the largest factor being CYP2C19 phenotype. In addition to phenotype, and after incorporating all PK covariates, moderate inter-individual variability persists. Due to PK variability, an ideal balance between reducing the Valsalva left ventricular outflow tract gradient (VLVOT) while maintaining the patient's left ventricular ejection fraction (LVEF) has been developed, and an echocardiography (ECHO)-based titration regimen has been developed. Modeling and simulation analyses have been performed to further evaluate dose titration by CYP2C19 phenotype.

[0850] In addition, an exposure-response simulation-based approach was utilized to investigate multiple titration regimens using a uniform distribution of CYP2C19 phenotypes to allow for additional sensitivity in assessing the performance of the titration regimen for each phenotype at the terminal. The evaluation included genotype-specific dosing and titration, adjustment of the starting dose by 2.5 mg, and additional monitoring intervals. For each dosimetry studied, the key objectives remained consistent: limiting the percentage (%) of simulated patients experiencing LVEF <50% while incrementally titrating to achieve VLVOT <30 mmHg. This example outlines the evaluation of the following 3 titration regimens.

[0851] The methods used to perform the simulations are described below. To investigate the described scenarios, 5000 virtual oHCM patients were simulated, with approximately 1000 simulated patients from each of the five CYP2C19 phenotypes: poor metabolizers (PM), intermediate metabolizers (IM), normal metabolizers (NM), rapid metabolizers (RM), and ultra-rapid metabolizers (UM). To construct the distribution of simulated patient covariates, the covariate set was selected from the set of actively treated subjects in studies MYK-461-005 (EXPLORER-HCM, NCT03470545) and MYK-461-007 (MAVA-LTE, for patients with oHCM, NCT03723655) and stratified by phenotype.

[0852] The same 5000 simulated patients were used in the simulations for each regimen to allow for a robust comparison of the performance of each simulated regimen according to metabolizer status and to control for patient covariates or residual variability from week to week that could account for differences between regimens.

[0853] Each regimen was simulated for 104 weeks, and the simulation code was designed to simulate the regimen of interest as closely as possible. For any patient who needs a dose interruption, an additional visit is added after 4 weeks (if this is not part of the regimen) to assess whether the simulated patient meets the criteria for restarting therapy. If they do not meet the criteria, they remain off-therapy for another 4 weeks, and if there is no planned visit, they are "forced" to restart treatment after 4 weeks (a total of 8 weeks later) (i.e., the simulation code implements restarting treatment without a visit after 4 weeks, which is a simplification of the clinical implementation of the titration regimen, which stipulates that treatment is restarted after 4-6 weeks of dose interruption). Patients restart with the next available lower dose intensity, and if stopped at 2.5 mg, they restart with the same 2.5 mg dose.

[0854] The simulations described in each section below have been arranged to provide the following key items:

[0855] Table showing the percentage of patients meeting LVEF ≤ 50% at selected time points over 104 weeks stratified by CYP2C19 metabolizer status / phenotype

[0856] Table showing the percentage of patients meeting LVOT ≤ 30 mmHg at the same time point during 104 weeks stratified by CYP2C19 metabolizer status / phenotype

[0857] Table showing the percentage of patients with mavacetal plasma concentrations >1000 ng / mL stratified by CYP2C19 metabolizer status / phenotype at the same time point over 104 weeks

[0858] Graph showing each of the key safety and efficacy thresholds (LVEF ≤ 50%, LVOT ≤ 30 mmHg, percentage of patients with mavaketide plasma concentration > 700 ng / mL, and mavaketide plasma concentration > 1000 ng / mL) stratified by CYP2C19 metabolizer status / phenotype

[0859] Dose distribution per CYP2C19 metabolizer status / phenotype at Week 104 stratified by CYP2C19 metabolizer status / phenotype.

[0860] Protocol #1: First proposed titration protocol using a unified CYP2C19 stratification

[0861] For this situation, the recommended ECHO-based dosimetry is as follows:

[0862] Each patient started therapy with a dose of 5 mg of mavacetib once daily.

[0863] All patients returned at Week 4 to assess whether they met criteria for dose interruption (LVEF <50%) or dose reduction with VLVOT <20 mmHg.

[0864] All patients returned at Week 12 for the opportunity for incremental titration (for patients with LVEF ≥ 55% and VLVOT ≥ 30 mmHg).

[0865] Patients who had a dose interruption at Week 4 returned 4 weeks later to assess whether they met LVEF criteria to restart therapy at the next lower dose (if restored LVEF ≥ 50%). This criteria was applied at each visit.

[0866] Patients who were titrated at week 12 returned 4 weeks later for assessment of LVEF and LVOT gradient. After this 4-week follow-up, the next visit was scheduled 12 weeks later (week 28) for the next titration opportunity and every 12 weeks thereafter (unless there was a dose titration or interruption, which would result in an additional 4-week follow-up).

[0867] After the Week 12 visit, patients who had no dose changes were evaluated at the 12-week visit, every 12 weeks thereafter until Week 52, and every 24 weeks from Week 52 to Week 104.

[0868] After week 40, all patients followed the same visit schedule: 12 weeks later, at week 52, and every 24 weeks thereafter. To account for the 4-week follow-up only for patients undergoing up-titration or dose interruption in the clinic, all simulated patients were assessed 4 weeks after the quarterly (12-week) or semiannual (24-week) visits.

[0869] Another incremental titration cannot be performed within 12 weeks.

[0870] To simplify the coding, a “mandatory restart” was implemented 8 weeks after a dose interruption if the patient did not meet the LVEF ≥ 50% criteria at the coded 4-week follow-up. This simplification was implemented four times, once at week 20 and three more times between weeks 40 and 104.

[0871] Table 5 shows the percentage of patients achieving LVEF ≤ 50% at selected time points during the 104 weeks stratified by phenotype. Overall, the highest percentage of patients with LVEF ≤ 50% was based on phenotypic status, with the highest incidence in PM (10.2% at week 24) and the lowest incidence in UM (< 2% at all time points). This relationship was also seen in the LVOT, with the highest percentage of patients meeting LVOT ≤ 30 mmHg in PM and the lowest percentage in Um (Table 6). Across all phenotypes, > 60% of patients met LVOT ≤ 30 mmHg after week 18.

[0872] Table 7 shows that the percentage of patients achieving mavaketide plasma concentrations >1000 ng / mL was generally low, with no more than 4% of patients exceeding this threshold across all phenotypes. Figure 13 depicts key safety and efficacy thresholds over the 104-week time period, including mavaketide plasma concentrations >700 ng / mL. The dose distribution depicted in Table 8 shows that at Week 104, the doses assigned across all phenotypes in the simulated patients were widely distributed, indicating that no single dose strength is appropriate for all patients using the proposed posology.

[0873] Table 5: Regimen #1: Percentage of patients achieving LVEF ≤ 50% at each time point during 104 weeks of dosing, stratified by phenotype

[0874] week PM IM NM RM UM 4 1.81 0.292 0.0993 0.1 0.103 8 4.23 0.68 0.199 0.1 0 10 5.84 1.07 0.0993 0.301 0 12 7.04 0.875 0.0993 0 0 18 7.75 1.65 1.09 0.602 0.103 24 9.96 2.33 1.09 0.903 0.411 30 4.83 2.33 1.09 0.702 0.514 36 6.04 2.62 1.29 0.903 0.925 48 4.93 1.26 1.89 0.903 0.308 72 9.26 2.04 1.59 1.3 0.822 104 5.23 1.46 2.09 1.5 1.03

[0875] Table 6: Percentage of patients achieving LVOT ≤ 30 mmHg at each time point during the 104-week dosing period of Regimen #1, stratified by phenotype

[0876] week PM IM NM RM UM 4 75.6 55.8 48.2 49.2 38 8 84.7 62.8 48.6 51.2 39 10 87.3 65.1 49.8 51.1 38 12 87.5 63 48.3 49.6 38 18 90.5 77.2 67.8 66.7 59.3 24 91.4 77.6 67.1 66.2 61.9 30 90.6 83.7 76.6 78.1 71.9 36 91.8 83.8 80.1 78 75 48 93.1 87.7 79.6 83.1 79.2 72 92.7 89.7 84.2 87 81.1 104 94.1 90.4 88 87.9 82.7

[0877] Table 7: Regimen #1: Percentage of patients achieving mavaketide plasma concentrations >1000 ng / mL at each time point during 104 weeks of dosing, stratified by phenotype

[0878] week PM IM NM RM UM 4 0.201 0 0 0 0 8 1.01 0 0 0 0 10 2.21 0 0 0 0 12 3.42 0 0 0 0 18 3.52 0.292 0 0.201 0 24 5.23 0.68 0.199 0.502 0 30 3.12 0.583 0.199 0.401 0.103 36 3.92 1.07 0.397 0.401 0.103 48 2.41 1.17 0.695 0.201 0 72 3.52 1.26 1.09 0.201 0.206 104 1.81 1.36 0.497 0.401 0.206

[0879] 13 (AD) shows the time course of the percentage of patients with LVEF ≤ 50%, VLVOT ≤ 30 mmHg, mavaketal plasma concentrations > 700 ng / mL, and mavaketal plasma concentrations > 1000 ng / mL according to Protocol #1 (104 weeks treatment duration).

[0880] Table 8: Regimen #1: Dose distribution at Week 104, stratified by phenotype

[0881]

[0882]

[0883] Option #2: Secondary Dosimetry with Additional ECHO Monitoring

[0884] This dosimetry maintains some similarities to the originally proposed dosimetry in that it represents a "unified" dosimetry for all patients, with the same starting dose (5 mg), LVEF criteria for up- and down-titration, and VLVOT criteria for up- and down-titration. Figure 4-6 The dosimetry was consistent with that in Protocol #1. Major changes in dosimetry compared to Protocol #1 included: all patients had an additional visit at Week 8 with the opportunity to titrate down; patients who could not tolerate the lowest dose of mavaketide (as defined by patients achieving LVEF <50% twice during treatment at the 2.5 mg dose) had the opportunity to permanently stop; and monitoring continued at 3-month intervals into the second year of treatment. At the Week 8 visit, an additional opportunity to titrate down was implemented for patients who were not titrated down at Week 4 and met the VLVOT <20 mmHg criteria for patients who were still on 5 mg. Simulation implementation was consistent with the approach outlined above. In addition, after the first titration opportunity at Week 12, all patient visits were synchronized to every 12 weeks, rather than 12 weeks after their last visit. In the second year, visits were maintained every 12 weeks, rather than every 24 weeks.

[0885] Table 9 shows the percentage of patients achieving LVEF ≤ 50% at selected time points during the 104 weeks stratified by phenotype. Overall, the highest percentage of patients with LVEF ≤ 50% was based on phenotypic status, with the highest incidence in PM (4.2% at Week 8) and the lowest incidence in UM (≤ 1% for all time points). This relationship was also seen in the LVOT, with the highest proportion of patients meeting LVOT ≤ 30 mmHg in PM and the lowest proportion in UM (Table 10). In all phenotypes except UM, > 60% of patients met LVOT ≤ 30 mmHg after Week 18.

[0886] Table 11 shows that the percentage of patients achieving mavaketide plasma concentrations >1000 ng / mL was generally low, with no more than approximately 2% of patients exceeding this threshold across all phenotypes. Figure 14 depicts key safety and efficacy thresholds over the 104-week period, including mavaketide plasma concentrations >700 ng / mL. The dose distribution depicted in Table 12 shows that doses remained widely distributed across all phenotypes and the final distribution was relatively consistent with the original posology, with the exception of approximately 10% of PM who permanently discontinued during treatment. This criterion appears to have minimal impact on all other metabolizer phenotypes and improves the overall benefit / risk while appropriately identifying those patients who may not be able to tolerate the lowest available dose intensity. Based on the simulated dose distribution below, this reflects approximately 10% of the PM population and 0.3% of the IM population. Given the CYP2C19 phenotype distribution in the EU population, this criterion would exclude / permanently discontinue <0.5% of patients overall.

[0887] Table 9: Regimen #2: Percentage of patients achieving LVEF ≤ 50% at each time point during 104 weeks of dosing, stratified by phenotype

[0888] week PM IM NM RM UM 4 1.81 0.292 0.0993 0.1 0.103 8 4.23 0.68 0.199 0.1 0 10 2.82 0.389 0 0 0 12 2.21 0.0972 0 0 0 18 3.23 0.875 0.794 0.401 0.103 24 3.79 1.36 1.09 0.702 0.206 30 4.03 1.85 1.19 0.903 0.308 36 3.26 2.33 1.69 0.702 0.822 48 2.88 2.43 1.09 1.3 1.13 72 2.94 1.95 1.19 1.31 1.13 104 2.8 2.73 0.993 0.803 0.719

[0889] Table 10: Percentage of patients achieving LVOT ≤ 30 mmHg at each time point during the 104-week dosing period of regimen #2, stratified by phenotype

[0890]

[0891]

[0892] Table 11: Regimen #2: Percentage of patients achieving mavaketide plasma concentrations >1000 ng / mL at each time point during 104 weeks of dosing, stratified by phenotype

[0893] week PM IM NM RM UM 4 0.101 0 0 0 0 8 1.11 0 0 0 0 10 0.302 0 0 0 0 12 0.302 0 0 0 0 18 1.01 0.0972 0 0.1 0 24 2.05 0.583 0.199 0.401 0 30 1.65 0.292 0.497 0.1 0.103 36 2 0.68 0.596 0.201 0.103 48 2.24 0.875 0.298 0.301 0 72 2.4 0.974 0.993 0.502 0.103 104 2.13 1.36 1.09 0.502 0.103

[0894] 14(AD) shows the time course of the percentage of patients with (A) LVEF <= 50%, (B) VLVOT <= 30 mmHg, (C) mavaketal plasma concentration > 700 ng / mL, and (D) mavaketal plasma concentration > 1000 ng / mL according to regimen #2 (104 weeks treatment duration).

[0895] Table 12: Regimen #2: Dose distribution at Week 104, stratified by phenotype

[0896] CYP DC 0mg 2.5mg 5mg 10mg 15mg PM 10.16 0.00 50.20 34.10 7.04 0.50 IM 0.29 0.00 15.26 37.90 33.62 13.02 NM 0.00 0.00 7.25 25.62 38.23 28.90 RM 0.10 0.00 7.62 27.68 35.51 29.09 UM 0.00 0.00 3.70 15.72 34.12 46.45

[0897] Option #3: Lower starting dose with additional evaluation of ECHO monitoring

[0898] This regimen remained the same as defined above as "Regimen 2", but with a lower starting dose of 2.5 mg. This regimen was evaluated to assess whether simple recommendations, such as a lower starting dose, could be made for patients with known CYP2C19 PM. For this simulation, all patients were started at a 2.5 mg starting dose, but the intent was to assess whether a certain subgroup phenotype could benefit from a lower starting dose without other modifications to the titration regimen.

[0899] Table 13 shows the percentage of patients achieving LVEF ≤ 50% at selected time points during the 104 weeks stratified by phenotype. Overall, the highest percentage of patients with LVEF ≤ 50% was based on phenotypic status, with the highest incidence in PM (4.9% at Week 24) and the lowest incidence in UM (≤ 1% for all time points). This relationship was also seen in the LVOT, with the highest proportion of patients meeting LVOT ≤ 30 mmHg in PM and the lowest proportion in UM (Table 14). In all phenotypes except UM, > 60% of patients met LVOT ≤ 30 mmHg after Week 30.

[0900] Table 15 shows that the percentage of patients achieving mavaketide plasma concentrations >1000 ng / mL was generally lower but higher than in Scenario 2 above, where the percentage of patients exceeding this threshold across all phenotypes did not exceed approximately 2.6%. Figure 15 depicts key safety and efficacy thresholds over the 104-week period, including mavaketide plasma concentrations >700 ng / mL. The dose distribution shown in Table 16 is very consistent with the distribution obtained in Scenario 2 above, indicating that the same patients ultimately achieve similar individualized optimal doses over time. This regimen had a delayed efficacy for patients compared to Scenario 2 above, with no improvement in safety. The primary reason for this is that in Scenario 2, the introduction of an additional dose-down titration visit at Week 8 provided an increased opportunity for early dose-down titration for patients who may ultimately require a lower dose. Patients who started at lower doses, especially PM, eliminated the benefit of additional down-titration opportunities, and when they eventually up-titrated at week 12 or later, the duration of treatment without ECHO visits was prolonged compared with the first 12 weeks, resulting in a higher percentage of PM achieving LVEF ≤ 50% overall, but with later onset of treatment, i.e., at week 24 rather than week 8. Table 16 shows that at week 104, there was a wide distribution of doses across all phenotypes assigned in the simulated patients, indicating that no single dose intensity is appropriate for all patients using the proposed posology.

[0901] Table 13: Regimen #3: Percentage of patients achieving LVEF ≤ 50% at each time point during 104 weeks of dosing, stratified by phenotype

[0902]

[0903]

[0904] Table 14: Percentage of patients achieving LVOT ≤ 30 mmHg at each time point during the 104-week dosing period of regimen #3, stratified by phenotype

[0905] week PM IM NM RM UM 4 43.5 29 27 26 21.3 8 54.2 34.8 26 29.1 22.5 10 60.8 36.2 28.4 28.4 22 12 60.3 34.8 27 27.7 21.6 18 79.4 60 48.3 47.6 37.3 24 85.2 61.3 47.1 48 41 30 88.7 75.9 67.7 67.9 58.6 36 89 75.4 70.8 68 59.4 48 91.3 84.7 75.9 77.6 71.6 72 91.6 90 80.6 83.7 81 104 93.8 92.2 85.6 87.9 84.5

[0906] Table 15: Regimen #3: Percentage of patients achieving mavaketide plasma concentrations >1000 ng / mL at each time point during 104 weeks of dosing, stratified by phenotype

[0907]

[0908]

[0909] 15(AD) shows the time course of percentage of patients with (A) LVEF <= 50%, (B) VLVOT <= 30 mmHg, (C) mavaketal plasma concentration > 700 ng / mL, and (D) mavaketal plasma concentration > 1000 ng / mL according to regimen #3 (104 weeks treatment duration).

[0910] Table 16: Regimen #3: Dose distribution at Week 104, stratified by phenotype

[0911] CYP DC 0mg 2.5mg 5mg 10mg 15mg PM 9.56 0.00 50.10 35.21 6.74 0.50 IM 0.29 0.00 14.87 39.75 33.53 11.66 NM 0.00 0.00 7.25 26.71 38.43 27.61 RM 0.10 0.00 7.02 29.09 36.61 27.18 UM 0.00 0.00 4.01 15.93 35.35 44.71

[0912] Summarize

[0913] In summary, several titration schemes were evaluated to improve the proposed titration scheme. The schemes evaluated the monitoring frequency, phenotype-specific fixed dose, phenotype-specific starting dose, phenotype-specific titration rules, and permanent stopping criteria. The second proposed dosimetry (Schedule #2) was considered to provide the best benefit / risk for the entire population while improving safety specifically for PM. Scheme #3 was tested to evaluate whether simple modifications / recommendations could be made for patients with known CYP2C19 phenotype. For PM, the lower starting dose recommendation did not result in an improvement in benefit / risk. This resulted in a delay in the time to achieve VLVOT ≤ 30 mmHg and a higher percentage of patients with LVEF ≤ 50% at one visit. Although safety appeared to improve within the first 12 weeks, the overall percentage of patients achieving LVEF ≤ 50% was higher than in Scheme #2. However, this phenomenon occurred, as expected, after patients were incrementally titrated at Week 12. This highlights that simple modifications to the titration scheme, such as a lower starting dose, do not improve the safety of PM. Additional changes to dosing regimens based on phenotype may provide a small benefit for PMs but would introduce additional risk to the overall patient population in terms of label complexity, risk of medication errors, and their impact on safety. Balancing all of these factors, it was assessed that this unified posology in option #2 could improve benefit / risk without introducing excessive complexity to the label that could lead to unintended medication errors.

[0914] FIG. 16 (A and B) shows a comparison of the percentage of patients achieving LVEF less than 50% between Scheme #1 and Scheme #2. As can be seen from the figure, a lower percentage of patients (especially poor metabolizer patients) had an LVEF < 50% under Scheme #2. For example, about 10% of poor metabolizer (PM) patients and about 1.2% of non-PM patients had an LVEF < 50% at week 24 under Scheme #1, while about 3.8% of PM patients and about 0.85% of non-PM patients had an LVEF < 50% at week 24 under Scheme #2. In addition, about 7% of poor metabolizer (PM) patients and about 0.25% of non-PM patients had an LVEF < 50% at week 12 under Scheme #1, while about 2.2% of PM patients and about 0.025% of non-PM patients had an LVEF < 50% at week 12 under Scheme #2.

[0915] Example 3. Risk Evaluation and Mitigation Strategy (REMS)

[0916] I. REMS Goals

[0917] The goal of the Malvaketel Risk Evaluation and Mitigation Strategy (REMS) program is to mitigate the risk of heart failure due to systolic dysfunction.

[0918] Purpose:

[0919] 1. Monitor with regular echocardiograms to detect heart failure due to systolic dysfunction.

[0920] 2. Screen for drug interactions before each prescription.

[0921] II. REMS Requirements

[0922] REMS program administrators must ensure that healthcare providers, patients, pharmacies, and wholesaler-distributors comply with the following requirements:

[0923]

[0924]

[0925]

[0926]

[0927] REMS program administrators must provide training to healthcare providers who prescribe Mavaketal.

[0928] The training includes the following instructional materials:

[0929] Program Overview

[0930] Educational programs for healthcare providers and pharmacies

[0931] Healthcare provider knowledge assessment

[0932] The training must be available online, via email, and in hard copy by mail.

[0933] The REMS program administrator must provide training to pharmacies that dispense Malvaketal.

[0934] The training includes the following instructional materials:

[0935] Program Overview

[0936] Educational programs for healthcare providers and pharmacies

[0937] ·Pharmacy Authorized Representative Knowledge Assessment

[0938] The training must be available online, via email, and in hard copy by mail.

[0939] To support REMS operations, REMS program administrators must:

[0940] 1. Based on receipt of the Patient Registration Form, Patient Status Form, and the Pharmacy Drug Interaction and Consultation List, authorize the dispensing of medications for each patient according to the following schedule:

[0941] · For initial dispensing: If the Patient Registration Form and Pharmacy Drug Interaction and Counseling Checklist are not completed, the patient is not authorized to receive the medication until the completed forms are received.

[0942] · For subsequent dispensing: If a Patient Status Form (as described in the healthcare provider and pharmacy education program) is not received within 3 calendar days of the last day of the week in which the echocardiogram was due, and the pharmacy Drug Interactions and Counseling Checklist is not completed prior to each dispensing, the patient is not authorized to receive the medication until the completed form is received.

[0943] 2. Establish and maintain a REMS website. The REMS website must include functionality to complete healthcare provider and pharmacy authentication and registration online; functionality to register and manage patients online, including completing the pharmacy drug interaction and consultation checklist and patient status form; functionality to review patient registration and authorization status and healthcare provider authentication status and obtain dispensing authorization; and the option to print prescription information, medication guides, and REMS materials. All product websites for consumers and healthcare providers must include a prominent REMS-specific link to the REMS program website. The REMS program website may not link back to promotional product websites.

[0944] 3. Make the REMS website fully operational and all REMS materials available through the website and the Mavaketee REMS Call Center.

[0945] 4. Establish and maintain a REMS call center for REMS participants.

[0946] 5. Establish and maintain a validated, secure database of all REMS Participants registered and / or certified in the Mavaketal REMS.

[0947] 6. Ensure healthcare providers and pharmacies are able to complete the certification process online and via fax.

[0948] 7. Ensure that healthcare providers are able to complete the patient registration process online and via fax.

[0949] 8. Ensure healthcare providers are able to complete the Patient Status Form online and by fax.

[0950] 9. Ensure the pharmacy is able to record prescription dosages and complete the pharmacy drug interaction and consultation checklist online and via fax.

[0951] 10. Ensure pharmacies can obtain dispensing authorizations online and by phone.

[0952] 11. Provide a program overview, a healthcare provider and pharmacy education program, and a healthcare provider enrollment form or pharmacy enrollment form to healthcare providers who (1) attempt to prescribe or dispense Malvaketamine but are not yet certified or (2) inquire about how to become certified.

[0953] 12. Notify healthcare providers and pharmacies within 1 business day of certification in the REMS.

[0954] 13. Once patient registration is complete, notify the healthcare provider within 1 business day.

[0955] 14. To provide certified healthcare providers with access to the database of their registered patients and certified pharmacies.

[0956] 15. Provide certified pharmacies with access to a database of certified healthcare providers and registered patients.

[0957] 16. Make the database of certified pharmacies accessible to authorized wholesaler-distributors.

[0958] To ensure that REMS participants comply with the REMS, the REMS program administrator must:

[0959] 17. Annually verify that the authorized representative's name and contact information matches the pharmacy's current designated authorized representative. If different, the pharmacy must recertify the new authorized representative.

[0960] 18. Maintain adequate records to demonstrate that REMS requirements have been met, including, but not limited to, records of mavacetal dispensing and dispensing, certification of healthcare providers and pharmacies, enrolled patients, completed patient status forms and pharmacy drug interaction and consultation lists, and audits of certified pharmacies and wholesaler-distributors. These records must be readily available for inspection by FDA.

[0961] 19. Establish and maintain a plan for addressing noncompliance with REMS requirements.

[0962] 20. Ongoing monitoring of healthcare providers, pharmacies, and wholesaler-distributors to ensure compliance with REMS requirements. If noncompliance is identified, corrective action is taken, including decertification.

[0963] 21. Audit pharmacies and wholesaler-distributors no later than 180 calendar days after certification and annually to ensure that all REMS processes and procedures are in place, functioning, and support REMS requirements.

[0964] 22. Based on the monitoring and evaluation of the Mavaket REMS, take reasonable steps to improve the operation of and comply with the REMS requirements.

[0965] III. REMS Evaluation Timeline

[0966] REMS program administrators must submit a REMS evaluation annually beginning on the date the REMS program is first approved. To facilitate the inclusion of as much information as possible while allowing a reasonable amount of time to prepare the submission, each evaluation should cover a reporting interval that is no earlier than 60 calendar days prior to the date the evaluation is submitted. REMS program administrators must submit each evaluation so that it is received by FDA on or before the due date.

[0967] IV. REMS Materials

[0968] The following materials are part of the MAVAKETEL REMS:

[0969] Registration Form

[0970] Healthcare Providers:

[0971] 1. Healthcare Provider Registration Form

[0972] patient:

[0973] 2. Patient Registration Form

[0974] pharmacy:

[0975] 3. Pharmacy Registration Form

[0976] Training and educational materials

[0977] Healthcare Providers:

[0978] 4. Educational programs for healthcare providers and pharmacies

[0979] 5. Program Overview

[0980] 6. Healthcare Provider Knowledge Assessment

[0981] patient:

[0982] 7. Patient Manual

[0983] pharmacy:

[0984] 8. Educational programs for healthcare providers and pharmacies

[0985] 9. Program Overview

[0986] 10. Knowledge Assessment for Pharmacy Authorized Representatives

[0987] Patient Care Form

[0988] 11. Patient Status Table

[0989] 12. Pharmacy Drug Interaction and Consultation Checklist

[0990] Other Materials

[0991] 13. REMS Website

[0992] Example 4. Simulation of drug-drug interactions

[0993] Purpose Statement: Mavaketide is a first-in-class, selective, allosteric, and reversible cardiac myosin inhibitor being developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy. Mavaketide is metabolized in the liver primarily by CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A previously developed fit-for-purpose physiologically based pharmacokinetic (PBPK) model was applied to explore the induction effects of rifampicin, a strong CYP3A4 / CYP2C19 inducer, and carbamazepine, a strong CYP3A4 inducer, on mavaketide exposure.

[0994] Methods: Modeling and simulation analysis were performed using Simcyp v19 (Certara). The mavaketal compound file was further validated against additional mavaketal Phase I clinical data in healthy volunteers. The DDI simulation study design included the introduction of an inducer dosing period to maximize the induction effect (rifampicin 600 mg QD for 7 days and carbamazepine 400 mg BID for 14 days), followed by a single mavaketal dose (15 mg), and continued inducer administration for another 2 months until the end of the virtual trial. All simulations used the default rifampicin and carbamazepine compound files provided in Simcyp Simulator (V19). The results of the simulations were stratified by 3 populations: healthy volunteers including all CYP2C19 phenotypes; healthy volunteers excluding CYP2C19 poor metabolizers (PMs); and healthy volunteers including only CYP2C19 PMs.

[0995] Data and results: Rifampicin DDI simulations observed that for all virtual populations evaluated, the AUC of Mavaketal 0-T Moderate decreases (geometric mean (GM) 60-69%), Cmax slightly decreased (GM 4-7%). In the presence of rifampicin induction, mavaketide clearance increased 2.5-fold to 3.2-fold. For all virtual populations, DDI simulations with carbamazepine resulted in mavaketide AUC 0-T (GM 13-30%) was slightly decreased and Cmax (GM 1%) was slightly decreased. In the presence of carbamazepine induction, mavacetide clearance increased 1.1-fold to 1.4-fold.

[0996] Conclusions: The Simcyp simulator was used to investigate the effects of strong CYP2C19 and / or CYP3A4 induction on mavaketela exposure based on the distribution of CYP2C19 phenotypes in a virtual population. Application of the model to understand the effects of strong CYP2C19 / CYP3A4 induction (rifampicin) revealed a modest reduction in mavaketela exposure in all populations. When mavaketela was co-administered with carbamazepine, a less potent strong CYP3A4 inducer, a weak induction effect was observed in all populations. Due to the reduction in mavaketela exposure when co-administered with strong CYP2C19 and / or CYP3A4 inducers, it is recommended that mavaketela is contraindicated with strong and moderate inducers of CYP2C19 and CYP3A4.

[0997] Example 5. Concomitant administration simulation

[0998] Purpose Statement: Mavaketel, a first-in-class, allosteric, selective, and reversible cardiac myosin inhibitor, is being developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy. A physiologically based pharmacokinetic (PBPK) model was used to explore the drug-drug interaction (DDI) status of Mavaketel with CYP2C19 and CYP3A4 induction. A PBPK model was further implemented to explore the potential effects of CYP2C19 and CYP3A4 inhibitors on the pharmacokinetics of Mavaketel.

[0999] Methods: All modeling was performed using Simcyp v19 software (Certara). A previously developed fit-for-purpose PBPK model was validated with additional clinical data from a mavaketal DDI study with the CYP3A4 inhibitor verapamil. Simcyp library compounds, ticlopidine, omeprazole, itraconazole, diltiazem, and cimetidine, were used to explore strong, moderate, and weak inhibition of CYP2C19 and CYP3A4, respectively, to understand the potential impact on mavaketal exposure at the maximum recommended clinical dose (15 mg QD). Simulations were performed under steady-state conditions for mavaketal and perpetrators, and DDI potential was explored based on CYP2C19 phenotype.

[1000] Data and Results: Simulations of strong CYP2C19 or CYP3A4 inhibition resulted in increases in geometric mean AUC up to 2.3-fold and 1.8-fold, respectively, and in geometric mean Cmax up to 1.6-fold and 1.5-fold, respectively, with inhibition showing phenotype-specific trends, such that strong CYP2C19 inhibition had the greatest effect on CYP2C19 ultra-rapid metabolizers, whereas strong CYP3A4 inhibition had the greatest effect on poor metabolizers ( Fig. 20A and B). Moderate CYP2C19 or CYP3A4 inhibition is expected to increase AUC by up to 1.6-fold and Cmax by up to 1.4-fold. Weak CYP2C19 inhibition is expected to increase AUC and Cmax by up to 1.4-fold and 1.2-fold, respectively, while weak CYP3A4 inhibition is expected to increase mavaketide exposure by less than 1.1-fold. The results are shown in Figure 20 (A and B).

[1001] Conclusions: Because CYP2C19 is a highly polymorphic enzyme, simulation results across CYP2C19 phenotypes were used to inform the dosimetry of mavaketide in the context of CYP2C19 and CYP3A4 DDI inhibition in patient populations. A contraindication for coadministration of moderate to strong CYP2C19 inhibitors with strong CYP3A4 inhibitors was proposed due to the increased exposure observed in simulations. Additional recommendations for weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors were also proposed, including initiating mavaketide treatment at the approved recommended dose for patients receiving a stable inhibitor regimen and reducing the mavaketide dose by one level for patients contemplating initiating therapy with these inhibitors. In summary, PBPK modeling was performed to inform mavaketide DDI inhibition recommendations taking into account differences in CYP2C19 phenotypes.

[1002] Example 6. Risk Assessment and Mitigation Strategy Requirements

[1003] A REMS must include the following:

[1004] Elements necessary to ensure safe use: Elements necessary to ensure safe use are needed as part of the REMS to mitigate the risk of heart failure due to systolic dysfunction listed in the drug label.

[1005] REMS include the following elements to mitigate this risk:

[1006] The healthcare provider has specific experience or training, or is specially certified

[1007] The pharmacy, practitioner, or healthcare organization that dispenses the drug is specifically certified

[1008] Dispensing drugs to patients with evidence or other documentation of safe use conditions

[1009] Every patient who uses the drug must be monitored

[1010] Implementation System: A REMS must include an implementation system to monitor, evaluate, and function to improve implementation of the elements of ensuring safe use (described above), which require that pharmacies that dispense drugs must be specifically certified and that drugs be dispensed to patients with documented conditions for safe use.

[1011] A REMS consists of elements to ensure safe use, an implementation system, and a timeline for submitting REMS evaluations.

[1012] The REMS evaluation plan must include but is not limited to the following: Program promotion and communication (data for only 1 year of evaluation)

[1013] 1. REMS Program Website

[1014] a) REMS website launch date

[1015] b) Total and unique visits to the REMS program website

[1016] c) The number and type of Mavaketal REMS materials downloaded or accessed

[1017] Plan implementation and operation

[1018] 2. REMS Call Center Report (provide data from two previous reporting periods, the current reporting period, and cumulative data)

[1019] a) Number of calls by stakeholder type (patient, healthcare provider, designee, pharmacy, wholesaler-distributor, other)

[1020] b) Overview of call reasons (e.g., registration issues) and stakeholder type (patient, healthcare provider, designee, pharmacy, other). Limit the overview to the top five reasons for calls for each stakeholder group.

[1021] c) If the outlined reason for the call indicates a complaint, include details about the nature of the complaint and whether the caller indicated a potential REMS burden or patient access issue

[1022] d) If the outlined reason for the call indicated an adverse event related to heart failure or a contraindicated medication or drug interaction, include details and the outcome of the call

[1023] e) Percentage of calls answered by the REMS call center within 20 minutes

[1024] f) Shortest waiting time for answering a call, longest waiting time for answering a call, and average time for answering a call

[1025] g) Percentage of calls to the REMS call center where the caller abandoned the call before the call was answered

[1026] f) Minimum waiting time before abandoning a call, maximum waiting time before abandoning a call, and median waiting time before abandoning a call

[1027] 3. Plan implementation (data for only one year of evaluation is provided)

[1028] a) Date when Mavaketei was first commercially available

[1029] b) For each stakeholder (health care provider, designee, pharmacy, patient), the date they were certified

[1030] c) The date the Mavaketee REMS call center is established and fully operational

[1031] 4. REMS certification and registration (provide data from two previous reporting periods, the current reporting period, and cumulative data)

[1032] a) Healthcare Providers:

[1033] i. Number of newly certified health care providers and number of active (i.e., filled at least one prescription during the reporting period) health care providers stratified by certification (e.g., MD, DOS, Nurse Practitioner, Physician Assistant, Other), specialty (e.g., Cardiology, Electrophysiology, Geneticist, Other), and geographic region (as defined by the U.S. Census). If “Other” accounted for >10% of respondents, the most common specialty identified was provided. Specific identification and classification of whether a specialty was in cardiology or non-cardiology

[1034] b) Number of designated personnel stratified by role (e.g., RPh / PharmD, RN, NP, or PA)

[1035] i. Healthcare provider and designee authentication method (online or fax)

[1036] c) Pharmacy

[1037] i. Number of newly certified pharmacies

[1038] ii. Number of active pharmacies (i.e. those that have dispensed Mavaket

[1039] d) Patients

[1040] i. Number of newly registered patients and number of active (i.e., received at least one Mavaketele dispensing) patients stratified by the composite variables of age, sex, and geographic region. The minimum and maximum age of the registered patients are provided. For the sex / age variables, the following age ranges are used: under 18 years, 18-40 years, 41-60 years, 61 years and older

[1041] e) Wholesaler-Distributor

[1042] i. The number of newly signed wholesaler-distributors and the number of active (i.e. already delivering Mavaket) wholesaler-distributors

[1043] 5. REMS compliance (provide data from two prior reporting periods, the current reporting period, and cumulative data)

[1044] a) A copy of the noncompliance plan, including the noncompliance criteria for healthcare providers, pharmacies, and wholesaler-distributors, the actions taken to address the noncompliance for each instance, and which events led to the decertification of the Mavaketal REMS (beginning with the 1-year assessment and annually thereafter)

[1045] b) Audit

[1046] i. Copies of audit plans for pharmacies and wholesalers / distributors

[1047] ii. Reporting of audit results for each stakeholder (pharmacies and wholesalers-distributors)

[1048] iii. The number of audits expected and the number of audits conducted.

[1049] iv. Record relevant personnel completing training

[1050] v. Documented processes and procedures in place to comply with the Mavaketal REMS

[1051] vi. Verify that the site-designated authorized representative for each audited stakeholder remains the same. If different, document that the pharmacy has been recertified with the new authorized representative’s name and contact information

[1052] vii. Number and type of deficiencies found for each group of audited stakeholders as a percentage of audited stakeholders.

[1053] viii. For each pharmacy audited, the number of deficiencies below (the numerator) divided by the number of medications dispensed at the pharmacy audited (the denominator):

[1054] The healthcare provider was not certified and dispensed the prescription

[1055] The patient was not registered and the prescription was not dispensed

[1056] Failure to complete the drug interaction and counseling checklist and dispense a prescription

[1057] Audit of drug interactions and consultation lists to identify medications that were dispensed but required actions were not taken

[1058] Authorisation refused and prescription dispensed

[1059] ix. Number of stakeholders who successfully completed Corrective and Preventive Action (CAPA) plans for those stakeholders who identified deficiencies, and percentage of stakeholders who requested CAPA plans

[1060] x. Description of actions taken for any stakeholders who did not complete the CAPA plan

[1061] c) Healthcare provider noncompliance (for each noncompliance incident, source of report, incident description, incident root cause analysis, and corrective actions taken)

[1062] i. Number of healthcare providers not complying with the requirements of the Mavaketal REMS program. Provide the percentage of active healthcare providers.

[1063] ii. The number of health care providers that were decertified and the reason for decertification, also provided as a percentage of active health care providers. Include whether any health care providers were recertified.

[1064] d) Pharmacy (for each non-compliance incident, source of report, incident description, root cause analysis, and corrective actions taken)

[1065] i. The number of pharmacies detected to be non-compliant with the Mavaketal REMS (numerator) divided by the number of all pharmacies dispensing Mavaketal (denominator)

[1066] ii. The number of uncertified pharmacies dispensing Malvakettai (numerator) divided by the number of all pharmacies dispensing Malvakettai (denominator). The estimated compliance rate is 99.9%.

[1067] iii. The number of Malvaketella prescriptions dispensed by uncertified pharmacies (numerator) divided by the number of all Malvaketella prescriptions dispensed (denominator) and the actions taken to prevent future recurrence. The estimated compliance rate is 99.9%

[1068] iv. The number of dispensed Malvaketal prescriptions written by uncertified healthcare providers (numerator) divided by the number of all dispensed prescriptions (denominator). For dispensed prescriptions written by uncertified healthcare providers, provide a root cause analysis and actions taken to prevent future recurrence. The expected compliance rate is 99.9%.

[1069] v. The number of Mavaketele prescriptions dispensed to non-enrolled patients (numerator) divided by the number of all prescriptions dispensed (denominator). For prescriptions dispensed to non-enrolled patients, provide a root cause analysis and actions taken to prevent future recurrence. The estimated compliance rate is 99.9%.

[1070] vi. The number of Mavaketek prescriptions dispensed to non-enrolled patients based on prescriptions from uncertified healthcare providers (numerator) divided by the number of all prescriptions dispensed (denominator). For prescriptions dispensed to non-enrolled patients based on prescriptions from uncertified healthcare providers, provide a root cause analysis and actions taken to prevent future recurrence. The expected compliance rate is 99.9%.

[1071] vi. The number of times a Malvaketal prescription was dispensed due to a certified pharmacy circumventing the Malvaketal REMS authorization process (numerator) divided by all certified pharmacies (denominator). Provide a root cause analysis and include a description of how the incident was identified and any corrective actions taken. The expected compliance rate is 99.9%.

[1072] vii. The number of pharmacies that were decertified, the reasons for decertification, and the actions taken to address noncompliance. Provided as a ratio of the number of pharmacies that were decertified (numerator) divided by the number of all certified pharmacies (denominator).

[1073] e) Wholesalers-Distributors (For each incident of noncompliance, source of report, incident description, root cause analysis, and corrective actions taken)

[1074] i. The number of contracted wholesalers-distributors detected to be non-compliant with the Mavaketal REMS (numerator) divided by the number of contracted wholesalers-distributors (denominator)

[1075] ii. The number of wholesaler-distributors whose distribution has been suspended, the reasons for the suspension, and the actions taken to address the non-compliance

[1076] iii. The number of times Mavaketal was distributed to non-certified pharmacies (numerator) divided by the number of times Mavaketal was distributed (denominator)

[1077] 6. Utilization data (provide data for two previous reporting periods, the current reporting period, and cumulative data)

[1078] a) Number of prescriptions dispensed (new fills and refills), stratified by:

[1079] i. Degree / credentials and geographic region of the healthcare provider

[1080] ii. Patient demographics (age and gender, and geographic region)

[1081] b) Number of prescriptions accepted and rejected (not authorized), stratified by:

[1082] i. Rejection reason and number of rejections (numerator) divided by all rejections (denominator)

[1083] The healthcare provider is not certified

[1084] Prescriptions written by designated personnel

[1085] Patient not registered

[1086] Patient status forms documenting echocardiograms were not submitted according to the appropriate schedule

[1087] Drug interactions and consultation checklists not completed

[1088] Drug interactions or contraindications were identified but no appropriate action was taken

[1089] Other reasons for rejection not included in the above categories

[1090] ii. Healthcare provider’s degree / qualifications and geographic region

[1091] c) The number of individual healthcare providers who wrote the dispensed prescriptions during the reporting period (active healthcare providers)

[1092] d) Number of individual patients receiving Mavaketele, stratified by age, sex and geographic region

[1093] 7. Burden on the healthcare system and / or barriers to care for patients

[1094] Report to the Mavaketee REMS call center any health care system burden or patient barriers to care. Evaluate whether the burden is attributable to REMS, insurance, health care availability, other

[1095] Safe use behavior

[1096] 8. Patient status table (provide data for two previous reporting periods, current reporting period, and cumulative data)

[1097] a) The number of patient status forms expected, received, and outstanding as of the REMS evaluation deadline

[1098] b) The number of first patient shipments sent prior to receipt of the patient registration form (numerator) divided by the number of all patients assigned Mavaketek (denominator). The estimated compliance rate is 99.9%.

[1099] c) The number of individual patients for whom a patient status form was submitted and whose healthcare provider confirmed that their echocardiogram had been reviewed (numerator) divided by the number of individual patients for whom a patient status form was submitted (denominator)

[1100] d) The number of individual patients for whom a patient status form has been submitted and for whom the healthcare provider has authorized treatment (the numerator) divided by the number of individual patients for whom a patient status form has been submitted (the denominator)

[1101] e) The number of patient status forms completed in the current reporting period that were not completed in the previous reporting period (numerator) divided by the number of patient status forms that were not completed in the previous reporting period (if applicable)

[1102] f) Number of patients whose echocardiograms were completed without medication due to authorization denial and reasons (e.g., medication not dispensed due to missing patient status form, insurance issues preventing medication dispensing, transportation issues preventing patient access to echocardiogram)

[1103] g) The number of patient status forms on which the healthcare provider indicated that the patient experienced a clinical heart failure event requiring hospitalization

[1104] h) The number of patient status forms on which the healthcare provider indicated that the patient experienced a decrease in LVEF to <50%

[1105] i) If the number of patients not authorized to receive Mavaketele is indicated on the patient status form

[1106] 9. Pharmacy drug interactions and consultation list (provide data for the previous two reporting periods, the current reporting period, and cumulative data)

[1107] a) The number of individual patients who completed the drug interaction and counseling checklist prior to first dispensing of Mavaketal (numerator) divided by the number of patients who initiated therapy with Mavaketal (denominator). The estimated compliance rate is 99.9%.

[1108] b) The number of prescriptions dispensed for which the drug interactions and counseling list was completed prior to dispensing (numerator) divided by the number of Malvaketal prescriptions dispensed (denominator). The estimated compliance rate is 99.9%.

[1109] c) The number of drug interaction and consultation lists that identified concomitantly contraindicated medications (numerator) divided by the total number of drug interaction and consultation lists completed (denominator)

[1110] d) For those drug interactions and advisory lists that identify concomitantly contraindicated medications, indicate the source of the drug interaction and the actions taken after contacting the health care provider, including:

[1111] i. Source

[1112] 1. Interacting medications prescribed by a certified healthcare provider / designee at Mavaket

[1113] 2. Interacting medications prescribed by other healthcare providers

[1114] 3. Interacting drugs purchased over the counter by the patient

[1115] ii. Actions taken

[1116] 1. Stop Mavaketae

[1117] 2. Stop taking contraindicated medications

[1118] c) The number of drug interaction and consultation lists identifying concurrent medications that require dose reduction (numerator) divided by the total number of drug interaction and consultation lists completed (denominator)

[1119] d) A list of drug interactions and consultations for those concomitant medications identified that required dose reduction, noting the source of the drug interaction and the actions taken after contacting the health care provider, including:

[1120] i. Source

[1121] 1. Interacting medications prescribed by a certified healthcare provider / designee at Mavaket

[1122] 2. Interacting medications prescribed by other healthcare providers

[1123] 3. Interacting drugs purchased over the counter by the patient

[1124] ii. Actions taken

[1125] 1. Stop Mavaketae

[1126] 2. Reduce the dose of Mavaketide

[1127] 3. Stop other medications

[1128] g) Any audit-derived or pharmacy-self-reported information indicating that patients received contraindicated medications while taking Malvacetta, expressed as the number of patients who received at least one Malvacetta delivery (dispensation) who also took the contraindicated medication (numerator) divided by the total number of patients who had at least one Malvacetta delivery (dispensation) (denominator). For all occurrences, include the name of the contraindicated medication, dose, and duration of therapy.

[1129] 10. Knowledge Assessment (only data from 1 and 2 year assessment reports are provided)

[1130] a) Number of completed healthcare provider knowledge assessments, including method of completion and number of completion attempts

[1131] b) Overview of the most frequently missed healthcare provider knowledge assessment questions

[1132] c) An overview of possible comprehension or perception issues identified using the healthcare provider knowledge assessment

[1133] d) The number of completed Pharmacy Authorized Representative Knowledge Assessments, including method of completion and number of completion attempts

[1134] e) Overview of the most frequently missed knowledge assessment questions for pharmacy authorized representatives

[1135] f) An overview of possible comprehension or perception issues identified using the pharmacy authorized representative knowledge assessment.

Claims

1. A method of treating a patient in need thereof with a myosin inhibitor, comprising: administering to the patient an initial dose of a myosin inhibitor for a first treatment period; administering a first reduced dose of the myosin inhibitor to the patient during a second treatment period when a first measure of left ventricular outflow tract obstruction in the patient taken at or near the end of the first treatment period is below a threshold, wherein the first reduced dose is less than the starting dose; and When a second measure of left ventricular outflow tract obstruction of the patient taken at or near the end of the second treatment period is below a threshold, a second reduced dose of the myosin inhibitor is administered to the patient during a third treatment period, wherein the second reduced dose is less than the dose of the myosin inhibitor administered immediately prior to the second reduced dose.

2. The method of claim 1, further comprising obtaining a first measure of left ventricular outflow tract obstruction in the patient taken at or near the end of the first treatment period; and A second measure of left ventricular outflow tract obstruction of the patient is obtained, taken at or near the end of the second treatment period.

3. The method of claim 1 or 2, wherein the second treatment period immediately follows the first treatment period.

4. The method of any one of claims 1-3, wherein the third treatment period is immediately subsequent to the second treatment period.

5. The method of any one of claims 1-4, wherein the dose of the myosin inhibitor administered to the patient is not increased until after the third treatment period.

6. The method of any one of claims 1-5, wherein the first measurement and the second measurement are taken using echocardiography.

7. The method of any one of claims 1-6, wherein the first measure of left ventricular outflow tract obstruction is a measure of the Valsalva LVOT gradient.

8. The method of claim 7, wherein the second measure of left ventricular outflow tract obstruction is a measure of the Valsalva LVOT gradient.

9. The method of claim 7 or 8, wherein the threshold is a Valsalva LVOT gradient of 20 mmHg.

10. The method of any one of claims 1-9, wherein the patient's risk of an adverse event is reduced compared to continuing to administer the myosin inhibitor at the starting dose.

11. The method of any one of claims 1-10, wherein the first treatment period is about 4 weeks.

12. The method of claim 11, wherein the second treatment period is about 4 weeks.

13. The method of claim 12, wherein the first treatment period, the second treatment period, and the third treatment period are each about 4 weeks.

14. The method of one of claims 1-13, wherein the patient suffers from symptomatic obstructive hypertrophic cardiomyopathy.

15. The method of claim 14, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy.

16. The method of any one of claims 1-15, wherein the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), Mavaketide, MYK-581, Afkate and pharmaceutically acceptable salts thereof.

17. The method of claim 16, wherein the myosin inhibitor is mavacetal or a pharmaceutically acceptable salt thereof.

18. The method of claim 16, wherein the myosin inhibitor is mavacetel.

19. The method of one of claims 18, wherein the starting dose is about 5 mg of mavacetel per day.

20. The method of claim 19, wherein the first reduced dose is less than about 5 mg of mavacetel per day.

21. The method of claim 20, wherein the first reduced dose is selected from the group consisting of about 2.5 mg of mavaketal per day, about 1 mg of mavaketal per day, or 0 mg of mavaketal per day.

22. The method of claim 21, wherein the second reduced dose is about 1 mg of mavaketal per day or 0 mg of mavaketal per day.

23. The method of claim 19, wherein the first reduced dose is about 2.5 mg of mavaketal per day and the second reduced dose is 0 mg of mavaketal per day.

24. The method of any one of claims 1-23, wherein the patient's left ventricular ejection fraction is greater than or equal to about 50% at or near the end of the first and second treatment periods.

25. A method of treating symptomatic obstructive hypertrophic cardiomyopathy in a patient in need thereof, comprising: administering to the patient a starting dose of 5 mg of mavacetide per day for a first treatment period, wherein the first treatment period is about 4 weeks; When the patient's Valsalva left ventricular outflow tract (LVOT) gradient taken at or near the end of the first treatment period is less than 20 mmHg, administering 2.5 mg of mavaketide per day to the patient for a second treatment period, wherein the second treatment period is about 4 weeks; and When the patient's Valsalva left ventricular outflow tract (LVOT) gradient taken at or near the end of the second treatment period is less than 20 mmHg, the patient is administered 0 mg of mavacetate per day for a third treatment period, wherein the third treatment period is about 4 weeks.

26. The method of claim 25, wherein the second treatment period immediately follows the first treatment period.

27. The method of claim 25 or 26, wherein the third treatment period immediately follows the second treatment period.

28. The method of any one of claims 25-27, further comprising administering 2.5 mg of mavaketide per day to the patient for a fourth treatment period when the patient's left ventricular ejection fraction measurement taken at or near the end of the third treatment period is greater than or equal to about 50%, wherein the fourth treatment period is about 4 weeks.

29. The method of claim 28, wherein the fourth treatment period immediately follows the third treatment period.

30. The method of any one of claims 25-29, wherein the patient has a LVEF greater than or equal to about 50%.

31. A method of treating a patient in need thereof with a myosin inhibitor, the method comprising the steps of: (a) administering an initial dose of myosin inhibitor during a first treatment period; (b) assessing left ventricular outflow tract obstruction in the patient to obtain a first assessment result and determining whether the first assessment result is below a first threshold; (c) administering a second dose during a second treatment period when the first assessment result is below a first threshold, wherein the second dose is less than the starting dose; (d) assessing left ventricular outflow tract obstruction in the patient to obtain a second assessment result and determining whether the second assessment result is below a second threshold; as well as (e) when the second assessment result is below a second threshold, administering a third dose during a third treatment period, wherein the third dose is less than the second dose.

32. The method of claim 31 further comprising the steps of: (f) at or near the end of the third treatment period, assessing left ventricular outflow tract obstruction of the patient to obtain a third assessment result and determining whether the third assessment result is greater than or equal to a third threshold, and assessing the patient's left ventricular ejection fraction (LVEF); and (g) administering a fourth dose during a fourth treatment period when the third assessment result is greater than or equal to a third threshold and the LVEF of the patient is greater than or equal to a LVEF threshold, wherein the fourth dose is greater than the third dose.

33. The method of claim 31 further comprising the steps of: (f) assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the third treatment period; and (g) administering a fourth dose during a fourth treatment period when the patient's LVEF is greater than or equal to a safety threshold, wherein the fourth dose is greater than the third dose.

34. The method of claim 32 or 33, further comprising the steps of: (h) at or near the end of the fourth treatment period, assessing the patient's left ventricular outflow tract obstruction to obtain a fourth assessment result and determining whether the fourth assessment result is greater than or equal to the fourth threshold, and assessing the patient's left ventricular ejection fraction (LVEF); as well as (i) when the fourth assessment result is greater than or equal to the fourth threshold and the LVEF of the patient is greater than or equal to the LVEF threshold, administering the fifth dose during a fifth treatment period, wherein the fifth dose is greater than the fourth dose.

35. The method of claim 31, wherein the first assessment and the second assessment are performed by non-invasive techniques.

36. The method of claim 32, wherein the third assessment is performed by non-invasive techniques.

37. The method of claim 35 or 36, wherein the non-invasive technique comprises echocardiography.

38. The method of claim 35 or 36, wherein the non-invasive technique comprises a cardiac imaging technique.

39. The method of any one of claims 35-38, wherein the non-invasive technique comprises measuring the LVOT gradient using a Valsalva maneuver.

40. The method of claim 39, wherein the first assessment result is a first Valsalva LVOT gradient and the second assessment result is a second Valsalva LVOT gradient.

41. The method of claim 40, wherein the first threshold and the second threshold are each a Valsalva LVOT gradient.

42. The method of claim 41, wherein the first threshold and the second threshold are each a Valsalva LVOT gradient of 20 mmHg.

43. The method of any one of claims 31-42, wherein the method reduces the risk of an adverse event.

44. The method of claim 43, wherein the adverse event is systolic dysfunction.

45. The method of claim 43, wherein the adverse event is heart failure.

46. ​​The method of any one of claims 43-45, wherein the patient's risk of an adverse event is reduced compared to continuing to administer the myosin inhibitor at the starting dose.

47. The method of any one of claims 31-46, wherein the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), Mavaketide, MYK-581 and Afkatete and pharmaceutically acceptable salts thereof.

48. The method of claim 47, wherein the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

49. The method of claim 47, wherein the myosin inhibitor is mavacetel.

50. The method of claim 49, wherein the starting dose is 5 mg of mavacetel per day.

51. The method of claim 50, wherein the second dose is less than 5 mg of mavacetel per day.

52. The method of claim 51, wherein the second dose is 2.5 mg of mavacetel per day.

53. The method of claim 51, wherein the third dose is less than 2.5 mg of mavacetel per day.

54. The method of claim 52, wherein the third dose is 0 mg of mavaketal per day or 1 mg of mavaketal per day.

55. The method of any one of claims 31-54, wherein the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

56. The method of claim 55, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

57. The method of claim 31, wherein a dose of 0 mg is administered during the third treatment period.

58. The method of any one of claims 31-57, wherein the dose of the myosin inhibitor administered to the patient is not increased until after the third treatment period.

59. The method of claim 32, wherein the LVEF threshold is 55%.

60. The method of claim 33, wherein the safety threshold is 50%.

61. The method of any one of claims 31-60, further comprising assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the first treatment period and at or near the end of the second treatment period.

62. The method of claim 61, further comprising temporarily stopping treatment when the LVEF assessment at or near the end of the first treatment period or the second treatment period is less than 50%.

63. The method of any one of claims 31-62, wherein the first treatment period is about four weeks and the second treatment period is about four weeks.

64. The method of claim 63, wherein the first treatment period is about four weeks, the second treatment period is about four weeks, and the third treatment period is about four weeks.

65. A method of using Mavaketal to treat a patient in need thereof, the method comprising the steps of: (a) during a first treatment period, administering 5 mg of mavacetide per day to the patient; (b) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient; (c) administering 2.5 mg of mavacetide per day to said patient daily during a second treatment period when said first Valsalva LVOT gradient is less than 20 mmHg; (d) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a second Valsalva LVOT gradient; and (e) when the second Valsalva LVOT gradient is less than 20 mmHg, administering 0 mg or 1 mg of Mavaketide daily to the patient for a third treatment period.

66. The method of claim 65, further comprising the steps of: (f) at or near the end of the third treatment period, assessing the patient's LVOT gradient using a Valsalva maneuver to determine a third Valsalva LVOT gradient and assessing the patient's left ventricular ejection fraction (LVEF); and (g) when the patient's third Valsalva LVOT gradient is greater than or equal to 30 mmHg and the LVEF is greater than or equal to 55%, administering 2.5 mg of mavacetide daily to the patient for a fourth treatment period.

67. The method of claim 65, further comprising the steps of: (f) assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the third treatment period; and (g) When the patient's LVEF is greater than or equal to 50%, administering 2.5 mg of Mavaketide daily to the patient for a fourth treatment period.

68. The method of claim 66 or 67, further comprising the steps of: (h) at or near the end of the fourth treatment period, assessing the patient's LVOT gradient using a Valsalva maneuver to determine a fourth Valsalva LVOT gradient and assessing the patient's left ventricular ejection fraction (LVEF); as well as (i) when the patient's fourth Valsalva LVOT gradient is greater than or equal to 30 mmHg and the LVEF is greater than or equal to 55%, administering 5 mg of Mavaketide daily to the patient for a fifth treatment period.

69. A method of administering mavaketide to a patient, wherein the patient suffers from oHCM, the method comprising the steps of: (a) administering to the patient a starting dose of 5 mg of mavacetide per day for a first treatment period; (b) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient; (c) when the first Valsalva LVOT gradient is less than 20 mmHg, administering 2.5 mg of Mavaketide per day to the patient for a second treatment period; (d) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a second Valsalva LVOT gradient; (e) when the second Valsalva LVOT gradient is less than 20 mmHg, administering 0 mg of mavacetide per day to the patient for a third treatment period; (f) evaluating the patient to determine a first left ventricular ejection fraction (LVEF); and (g) when the first LVEF is greater than or equal to 50%, administering 2.5 mg of mavacetir per day to the patient for a fourth treatment period.

70. The method of claim 69, further comprising the steps of: (h) evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a third Valsalva LVOT gradient, and evaluating the patient to determine a second left ventricular ejection fraction (LVEF); as well as (i) when the third Valsalva LVOT gradient is greater than or equal to 30 mmHg and the second LVEF is greater than or equal to 55%, administering 5 mg of mavacetide per day to the patient for a fifth treatment period.

71. The method of claim 69 or 70, wherein the patient's risk of contractile dysfunction and / or heart failure is reduced compared to continuing to administer the myosin inhibitor at the starting dose.

72. The method of any one of claims 69-71, wherein the first treatment period is about four weeks and the second treatment period is about four weeks.

73. The method of claim 72, wherein the third treatment period is about four weeks.

74. The method of claim 73, wherein the fourth treatment period is about twelve weeks.

75. The method of any one of claims 69-74, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

76. A method of administering mavaketide to a patient, wherein the patient suffers from oHCM, the method comprising the steps of: administering to the patient a starting dose of 5 mg of mavacetide per day for a first treatment period; assessing the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient; administering a second dose of mavacetel during a second treatment period, wherein if the first Valsalva LVOT gradient is less than 20 mmHg, the second dose is 2.5 mg per day, and wherein if the first Valsalva LVOT gradient is greater than or equal to 20 mmHg, the second dose is 5 mg per day; assessing the patient's LVOT gradient using a Valsalva maneuver to determine a second Valsalva LVOT gradient; A third dose of Mavaketide is administered during the third treatment period, wherein if the second Valsalva LVOT gradient is less than 20 mmHg, the third dose is less than the second dose, and the third dose is 2.5 mg, 1 mg, or 0 mg per day; and wherein if the first Valsalva LVOT gradient is greater than or equal to 20 mmHg, the third dose is the same as the second dose, and the third dose is 5 mg or 2.5 mg per day.

77. The method of claim 76, wherein the patient receives a third dose of 0 mg per day during the third treatment period; the method further comprising the steps of: evaluating the patient to determine left ventricular ejection fraction (LVEF); as well as A fourth dose of mavacetel is administered during the fourth treatment period, wherein if the LVEF is greater than or equal to 50%, the fourth dose is 2.5 mg per day, and wherein if the LVEF is less than 50%, the fourth dose is 0 mg per day.

78. The method of claim 76, wherein the patient receives a third dose of 1 mg per day, 2.5 mg per day, or 5 mg per day during the third treatment period; the method further comprising the steps of: evaluating the patient's LVOT gradient using a Valsalva maneuver to determine a third Valsalva LVOT gradient, and evaluating the patient to determine a left ventricular ejection fraction (LVEF); as well as A fourth dose of Mavaketide is administered during a fourth treatment period, wherein if the third Valsalva LVOT gradient is greater than or equal to 30 mmHg and the LVEF is greater than or equal to 55%, the fourth dose is greater than the third dose and the fourth dose is 2.5 mg, 5 mg, or 10 mg per day, and wherein if the third Valsalva LVOT gradient is less than 30 mmHg or the LVEF is less than 55%, the fourth dose is the same as the third dose and the fourth dose is 1 mg, 2.5 mg, or 5 mg per day.

79. The method of any one of claims 76-78, wherein the patient's risk of systolic dysfunction and / or heart failure is reduced compared to if the patient received continued administration of mavaketide at the starting dose.

80. The method of any one of claims 76-79, wherein the first treatment period is about four weeks and the second treatment period is about four weeks.

81. The method of claim 80, wherein the third treatment period is about four weeks.

82. The method of claim 81, wherein the fourth treatment period is about twelve weeks.

83. The method of any one of claims 76-82, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

84. A method of treating a patient in need thereof with a myosin inhibitor, comprising: administering to the patient an initial dose of a myosin inhibitor for a first treatment period; A second dose of a myosin inhibitor is administered to the patient for a second treatment period, wherein: The second dose is less than the starting dose if the patient's LVOT gradient taken at or near the end of the first treatment period is below a threshold, and If the patient's LVOT gradient taken at or near the end of the first treatment period is greater than or equal to the threshold, the second dose is the same as the starting dose; and A third dose of the myosin inhibitor is administered to the patient for a third treatment period, wherein: The third dose is less than the second dose if the patient's LVOT gradient taken at or near the end of the second treatment period is below the threshold, and If the patient's LVOT gradient taken at or near the end of the second treatment period is greater than or equal to the threshold, the third dose is the same as the second dose.

85. The method of claim 84, wherein the second treatment period is immediately followed by the third treatment period.

86. The method of claim 85, wherein the third treatment period is immediately subsequent to the second treatment period.

87. The method of any one of claims 84-86, further comprising administering to the patient a fourth dose of the myosin inhibitor for a fourth treatment period, wherein: If the third dose is less than the second dose, and the second dose is less than the starting dose, and a measurement of the patient's left ventricular ejection fraction taken at or near the end of the third treatment period is greater than or equal to about 50%, then the fourth dose is the same as the lowest dose previously administered and the fourth treatment period, and If the third dose is equal to the second dose and / or the second dose is equal to the starting dose, the fourth treatment period is longer than the third treatment period.

88. The method of claim 87, wherein the fourth treatment period immediately follows the third treatment period.

89. The method of any one of claims 84-88, wherein the first treatment period, the second treatment period, and the third treatment period are about four weeks.

90. The method of any one of claims 84-89, wherein the threshold value is 20 mmHg.

91. The method of any one of claims 84-90, wherein when the third dose is less than the second dose, and the second dose is less than the starting dose, and the measurement of the patient's LVEF taken at or near the end of the third treatment period is greater than or equal to about 50%, the fourth treatment period is about 4 weeks.

92. The method of any one of claims 84-90, wherein when the third dose is equal to the second dose and / or the second dose is equal to the starting dose, the fourth treatment period is about 12 weeks.

93. The method of any one of claims 84-92, wherein the patient has a LVEF greater than or equal to about 50%.

94. The method of any one of claims 84-93, wherein the LVOT gradient is a Valsalva LVOT gradient.

95. The method of any one of claims 84-94, wherein the patient's risk of an adverse event is reduced compared to continuing to administer the myosin inhibitor at the starting dose.

96. The method of any one of claims 84-95, wherein the first treatment period, the second treatment period, and the third treatment period are each about 4 weeks.

97. The method of any one of claims 84-96, wherein the patient suffers from symptomatic obstructive hypertrophic cardiomyopathy.

98. The method of claim 97, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy.

99. The method of any one of claims 84-98, wherein the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), Mavaketide, MYK-581, Afkate and pharmaceutically acceptable salts thereof.

100. The method of claim 99, wherein the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

101. The method of claim 99, wherein the myosin inhibitor is mavacetel.

102. The method of claim 101, wherein the starting dose is about 5 mg of mavacetel per day.

103. The method of claim 102, wherein the second dose is less than about 5 mg of mavaketal per day, or wherein the second dose is selected from the group consisting of about 2.5 mg of mavaketal per day, about 1 mg of mavaketal per day, or 0 mg of mavaketal per day.

104. The method of claim 103, wherein the third dose is less than about 2.5 mg of mavacetel per day or wherein the third dose is 1 mg per day or 0 mg per day.

105. The method of claim 104, wherein the second dose is about 2.5 mg of mavaketal per day and the third dose is 0 mg of mavaketal per day.

106. The method of any one of claims 84-105, wherein the fourth dose is selected from the group consisting of 2.5 mg, 5 mg, and 10 mg of mavaketel per day.

107. A method of treating a patient in need thereof with a myosin inhibitor, the method comprising: Administer a starting dose of myosin inhibitor at least once daily at the beginning of the initiation phase; and performing one or more assessments of left ventricular outflow tract obstruction in the patient during the initiation phase to obtain one or more assessment results; as well as Administration of the myosin inhibitor is discontinued based on the one or more evaluation results.

108. The method of claim 107, further comprising resuming administration of the myosin inhibitor after said cessation.

109. The method of claim 108, wherein administration is resumed after assessing the patient's LVEF, wherein administration is resumed when the LVEF is greater than or equal to a safety threshold.

110. The method of any one of claims 107-109, wherein the one or more assessments are performed by non-invasive techniques.

111. The method of claim 110, wherein the non-invasive technique comprises echocardiography.

112. The method of claim 110, wherein the non-invasive technique comprises a cardiac imaging technique.

113. The method of claim 110, wherein the non-invasive technique comprises measuring LVOT gradients using a Valsalva maneuver, and the one or more assessment results are one or more Valsalva LVOT gradients.

114. The method of claim 113, comprising stopping administration of the myosin inhibitor when the Valsalva LVOT gradient is less than 20 mmHg.

115. The method of any one of claims 110-114, comprising evaluating the patient's left ventricular outflow tract obstruction two or more times by non-invasive techniques during the initial stage to obtain two or more evaluation results.

116. The method of claim 115, wherein the non-invasive technique comprises measuring the LVOT gradient using a Valsalva maneuver, and the two or more assessment results are two or more Valsalva LVOT gradients.

117. The method of claim 116, comprising stopping administration of the myosin inhibitor when at least two of the two or more Valsalva LVOT gradients are below 20 mmHg.

118. The method of any one of claims 107-117, wherein the method reduces the risk of an adverse event in the patient.

119. The method of claim 118, wherein the adverse event is systolic dysfunction.

120. The method of claim 118, wherein the adverse event is heart failure.

121. The method of any one of claims 118-120, wherein the patient's risk of an adverse event is reduced compared to continued administration of the myosin inhibitor.

122. The method of any one of claims 107-121, wherein the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), Mavaketide, MYK-581 and Afkate, optionally in the form of pharmaceutically acceptable salts thereof.

123. The method of claim 122, wherein the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

124. The method of claim 122, wherein the myosin inhibitor is mavacetel.

125. The method of claim 124, wherein the starting dose is 5 mg of mavacetel per day.

126. The method of any one of claims 107-125, wherein the patient suffers from oHCM.

127. The method of any one of claims 107-126, wherein the duration of the initial phase is from about 4 weeks to about 6 months.

128. The method of claim 127, wherein the duration of the initial phase is from about 8 weeks to about 16 weeks.

129. The method of claim 109, wherein the safety threshold is 50%.

130. A method of using Mavaketal to treat a patient in need thereof, comprising the steps of: (a) at the beginning of the initiation phase, administering to the patient a starting dose of 5 mg per day of Mavaketide; and (b) assessing the patient's LVOT gradient two or more times at separate times during the initial phase using the Valsalva maneuver to obtain two or more Valsalva LVOT gradients; and (c) when each of the two or more Valsalva LVOT gradients is less than 20 mmHg, discontinuing administration of Mavaketel.

131. A method of treating a patient in need thereof with a myosin inhibitor, the method comprising: administering to said patient an initial dose of said myosin inhibitor; assessing said patient for left ventricular outflow tract obstruction at or near the end of two or more separate treatment periods to obtain two or more assessments; as well as A first reduced dose and subsequently a second reduced dose are administered based on the two or more assessment results, wherein the assessment results are below a threshold, wherein the first reduced dose is less than the starting dose, and the second reduced dose is less than the first reduced dose.

132. The method of claim 131, wherein the dose of the myosin inhibitor administered to the patient is not increased until the two or more assessments are completed at or near the end of the two or more separate treatment periods.

133. The method of claim 131 or 132, wherein the two or more assessments are performed by non-invasive techniques.

134. The method of claim 133, wherein the non-invasive technique comprises echocardiography.

135. The method of claim 133, wherein the non-invasive technique comprises a cardiac imaging technique.

136. The method of any one of claims 133-135, wherein the non-invasive technique comprises measuring the LVOT gradient using a Valsalva maneuver.

137. The method of claim 136, wherein the assessment result is the Valsalva LVOT gradient.

138. The method of claim 137, wherein the threshold is the Valsalva LVOT gradient.

139. The method of claim 138, wherein the threshold is a Valsalva LVOT gradient of 20 mmHg.

140. The method of any one of claims 131-139, wherein the method reduces the risk of an adverse event.

141. The method of claim 140, wherein the adverse event is systolic dysfunction.

142. The method of claim 140, wherein the adverse event is heart failure.

143. The method of any one of claims 140-142, wherein the patient's risk of an adverse event is reduced compared to continuing to administer the myosin inhibitor at the starting dose.

144. The method of any one of claims 131-143, wherein the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), Mavaketide, MYK-581, Afkate and pharmaceutically acceptable salts thereof.

145. The method of claim 144, wherein the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

146. The method of claim 144, wherein the myosin inhibitor is mavacetel.

147. The method of claim 146, wherein the starting dose is 5 mg of mavacetel per day.

148. The method of claim 147, wherein the first reduced dose is less than 5 mg per day.

149. The method of claim 148, wherein the second reduced dose is less than 2.5 mg per day.

150. The method of claim 148, wherein the first reduced dose is 2.5 mg of mavacetel per day.

151. The method of claim 150, wherein the second reduced dose is 1 mg per day or 0 mg per day of mavacetel.

152. The method of any one of claims 131-151, wherein the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

153. The method of claim 152, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

154. The method of any one of claims 131-153, wherein the two or more separate treatment periods include a first treatment period and a second treatment period, and wherein the two or more evaluation results include a first evaluation result at or near the end of the first treatment period and a second evaluation result at or near the end of the second treatment period.

155. The method of claim 154, further comprising administering the myosin inhibitor for a third treatment period after the second assessment.

156. The method of claim 154 or 155, wherein the dose of the myosin inhibitor administered to the patient is not increased until after the third treatment period.

157. The method of any one of claims 154-156, wherein the first treatment period is about four weeks and the second treatment period is about four weeks.

158. The method of claim 157, wherein the third treatment period is about four weeks.

159. The method of any one of claims 131-158, further comprising assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the two or more separate treatment periods.

160. A method of reducing the risk of heart failure with reduced ejection fraction resulting from administration of a myosin inhibitor to a patient, the method comprising the steps of: administering a myosin inhibitor to said patient; Temporarily stopping the administration of the myosin inhibitor when the patient's LVEF is less than 50%; When the patient's LVEF is greater than or equal to 50%, resuming administration of the myosin inhibitor to the patient; and When the patient's LVEF was less than 50% after resumption of administration, administration of the myosin inhibitor was permanently discontinued.

161. The method of claim 160, wherein the LVEF is determined by non-invasive techniques.

162. The method of claim 161, wherein the non-invasive technique is echocardiography.

163. The method of claim 161, wherein the non-invasive technique comprises a cardiac imaging technique.

164. The method of any one of claims 160-163, wherein resuming administration comprises administering the same dose that the patient received prior to temporarily stopping.

165. The method of any one of claims 160-163, wherein resuming administration comprises administering a dose lower than the dose the patient received prior to temporary cessation.

166. The method of any one of claims 160-163, wherein resuming administration comprises administering a minimum dose of a myosin inhibitor to the patient, wherein the minimum dose is the lowest dose of the myosin inhibitor approved by a government regulatory agency for administration to a patient.

167. The method of claim 166, wherein the government regulatory agency is an agency of the United States, the European Union, Switzerland, Japan, China, South Korea, Canada, Mexico, Australia, New Zealand, Brazil, Russia, Ukraine, Georgia, Vietnam, Singapore, Malaysia, Philippines, India, Indonesia, Israel, South Africa, Colombia, Costa Rica, Dominican Republic, Ecuador, Guatemala, El Salvador, Honduras, Egypt, Syria, Algeria, Kenya, Morocco, or Nigeria.

168. The method of any one of claims 160-167, wherein the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), Mavaketide, MYK-581 and Afkatete and pharmaceutically acceptable salts thereof.

169. The method of claim 168, wherein the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

170. The method of claim 168, wherein the myosin inhibitor is mavacetel.

171. The method of any one of claims 160-170, wherein the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

172. The method of claim 171, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

173. A method of reducing the risk of heart failure with reduced ejection fraction resulting from administration of mavaketide to a patient, the method comprising the steps of: administering Mavaketide to the patient at a dose of 2.5 mg per day; When the patient's LVEF is less than 50%, temporarily stop the administration of Mavaketide; When the patient's LVEF is greater than or equal to 50%, resuming administration of mavacetide to the patient at a dose of 2.5 mg per day; and When the patient's LVEF was less than 50% after resumption of dosing, mavacetal was permanently discontinued.

174. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of mavaketide, wherein the patient is not receiving concomitant administration of a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer.

175. A method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, wherein the patient is being treated with a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer, the method comprising: discontinuing administration of the strong or moderate CYP2C19 inducer or the strong or moderate CYP3A4 inducer to the patient; and A therapeutically effective amount of mavaketide is administered to the patient, thereby avoiding the use of mavaketide in combination with a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer.

176. A method of administering a myosin inhibitor to a patient initiating concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor while receiving myosin inhibitor therapy, the method comprising: administering a first daily dose of the myosin inhibitor during a first treatment period prior to initiating concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor; A second daily dose of the myosin inhibitor is administered during a second treatment period, the second daily dose being less than the first daily dose, wherein the patient is receiving concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor during the second treatment period.

177. The method of claim 176, further comprising assessing the patient's LVEF during the second treatment period and temporarily stopping administration of the myosin inhibitor if the LVEF is below a safety threshold.

178. The method of claim 177, wherein the safety threshold is 50%.

179. The method of claim 177, further comprising assessing the patient's LVEF and LVOT gradient after cessation of administration, and resuming administration of the first daily dose when the LVOT gradient is greater than or equal to a threshold and the LVEF is greater than or equal to a LVEF threshold.

180. The method of claim 179, wherein the threshold is 30 mmHg and the LVEF threshold is 55%.

181. The method of any one of claims 176-180, wherein the myosin inhibitor is selected from the group consisting of compounds of Group (I), compounds of Group (II), compounds of Group (III), Mavaketide, MYK-581 and Afkatete and pharmaceutically acceptable salts thereof.

182. The method of claim 181, wherein the myosin inhibitor is mavacetel or a pharmaceutically acceptable salt thereof.

183. The method of claim 181, wherein the myosin inhibitor is mavacetel.

184. The method of claim 183, wherein the first daily dose is 5 mg, 10 mg, or 15 mg of mavaketal and the second daily dose is 2.5 mg, 5 mg, or 10 mg of mavaketal.

185. The method of any one of claims 176-184, wherein the weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor is selected from the group consisting of cimetidine, ciprofloxacin, diltiazem, felbamate, omeprazole at a dose of 20 mg once daily, isoniazid, fluconazole, and verapamil.

186. The method of any one of claims 176-185, wherein the patient suffers from obstructive hypertrophic cardiomyopathy (oHCM).

187. The method of claim 186, wherein the patient suffers from symptomatic New York Heart Association (NYHA) class II-III oHCM.

188. The method of claim 177, wherein assessing the patient's LVEF during the second treatment period comprises assessing the patient's LVEF approximately four weeks after initiating the concomitant therapy.

189. The method of any one of claims 176-188, wherein the second treatment period is at least 12 weeks, and wherein the second daily dosage is not increased to a higher dose during at least the first 12 weeks of the second treatment period.

190. A method of treating HCM in a patient being administered a first daily dose of mavaketide, wherein the patient then requires concomitant treatment with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor in addition to mavaketide, the method comprising: In addition to administering the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, the patient is administered a second daily dose of mavaketide, the second daily dose being less than the first daily dose.

191. The method of claim 190, wherein the first daily dose is 5 mg, 10 mg, or 15 mg per day and the second daily dose is 2.5 mg, 5 mg, or 10 mg per day.

192. A method of initiating concomitant administration of mavaketide in a patient being administered a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, wherein the patient requires concomitant administration of mavaketide and the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, and wherein the patient is receiving stable therapy with the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, the method comprising: The patient is concomitantly administered mavacetide at a daily dose of 5 mg per day and a stable therapy of the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor.

193. A method of administering a myosin inhibitor to a patient initiating or increasing the dose of concomitant therapy with a negative inotropic drug while receiving myosin inhibitor therapy, the method comprising: (a) administering a therapeutically effective amount of a myosin inhibitor during a first treatment period; (b) continuing to administer the myosin inhibitor during a second treatment period, wherein during the second treatment period the patient initiates or increases the dose of concomitant therapy with a negative inotropic drug; and (c) providing echocardiographic monitoring of LVEF during said second treatment period.

194. The method of claim 193, wherein echocardiographic monitoring of LVEF is provided until a stable dose and clinical response is achieved.

195. The method of claim 193 or 194, further comprising providing close medical supervision during the second treatment period.

196. The method of any one of claims 193-195, wherein the myosin inhibitor is mavacetel.

197. A computer-implemented method that, when executed by data processing hardware, causes the data processing hardware to perform operations comprising: obtaining healthcare professional (HCP) evaluation records associated with the patient, the HCP evaluation records including the outcome of the procedure; using the HCP assessment record to determine whether the patient is authorized to receive a prescription authorization authorizing the use of a prescription medication; and When the patient is authorized to receive the prescribed medication: obtaining a pharmacy assessment record associated with the patient, the pharmacy assessment record including a medical condition of the patient; using the pharmacy assessment record to determine whether the pharmacy is authorized to dispense the prescription medication to the patient; as well as When the pharmacy is authorized to dispense the prescribed medication to the patient: Generate dispensing authorizations; and The dispensing authorization is transmitted to the pharmacy.

198. The method of claim 197, wherein the procedural results include echocardiographic results.

199. The method of claim 197 or 198, wherein at least one of the HCP assessment record and the pharmacy assessment record includes potential drug-drug interactions.

200. The method of any one of claims 197-199, wherein obtaining the HCP assessment record comprises retrieving the HCP assessment record from a database remote from the data processing hardware.

201. The method of any of claims 197-200, wherein determining whether the patient is authorized to receive the prescription authorization is in response to receiving a prescription request.

202. The method of any one of claims 197-201, wherein the dispensing authorization comprises: the amount of the prescribed medication that the patient is authorized to receive; as well as The time period during which the patient is authorized to receive the prescribed medication.

203. The method of any one of claims 197-202, wherein the operations further comprise, after the time period has elapsed: determining whether updated procedural results relevant to the patient are available; updating the dispensing authorization using the updated procedure results when the updated procedure results are available; as well as When the updated procedure result is not available, renewing the dispensing authorization is denied.

204. The method of any one of claims 197-203, wherein updating the dispensing authorization comprises at least one of: adjusting the amount of the prescribed medication that the patient is authorized to receive; and The time period during which the patient is authorized to receive the prescribed medication is adjusted.

205. The method of any one of claims 197-204, wherein the operation further comprises generating a report for a regulatory agency when the patient is not authorized to receive the prescription medication or when the pharmacy is not authorized to dispense the prescription medication to the patient.

206. The method of any one of claims 197-205, wherein the prescription medication comprises mavacetal.

207. A system comprising: Data processing hardware; as well as Memory hardware in communication with the data processing hardware, the memory hardware storing instructions which, when executed on the data processing hardware, cause the data processing hardware to perform the operations of any one of method claims 197-206.

208. A method of reducing the risk of heart failure due to contractile dysfunction in a patient being administered a myosin inhibitor, the method comprising: providing a data storage facility, the data storage facility comprising a database containing patient HCP assessment records and patient pharmacy assessment records, wherein each patient HCP assessment record comprises information regarding said patient's echocardiogram date, LVEF determined from said echocardiogram, VLVOT determined from said echocardiogram, experience of a clinical heart failure event, and risk of potential drug-drug interactions, and wherein each patient pharmacy assessment record comprises information regarding said patient's medical condition, concomitant medications and supplements, and potential drug-drug interactions; A central controller having one or more processors coupled to a communications network is provided, the central controller being coupled to the data storage facility to read data from and write data to the data storage facility over the network, wherein: The central controller controls the transmission of data to and reception of data from the data storage facility via the network, the central controller being programmed to output, via the network, an HCP authorization to prescribe the myosin inhibitor for the patient, wherein output of the HCP authorization is contingent upon satisfactory HCP information entered into each patient's HCP evaluation record regarding echocardiogram date, echocardiogram results, clinical heart failure event experience, and risk of drug-drug interactions, and wherein the central controller prevents output of the HCP authorization due to unsatisfactory HCP information, The central controller is further programmed to output a dispensing authorization for the myosin inhibitor to the patient via the network, wherein the output of the pharmacy authorization is contingent upon the output of the HCP authorization and satisfactory pharmacy information entered into each patient's pharmacy assessment record regarding the patient's medical condition, concomitant medications and supplements, and potential drug-drug interactions, and wherein the central controller prevents the output of the dispensing authorization due to unsatisfactory pharmacy information and / or lack of HCP authorization, and Therein, the central controller manages one or more aspects of reporting unsatisfactory information regarding clinical heart failure event experience to a regulatory agency or other supervisory body.

209. A computer-implemented method that, when executed by data processing hardware, causes the data processing hardware to perform an operation, the method comprising: obtaining healthcare professional (HCP) evaluation records associated with the patient, the HCP evaluation records including the outcome of the procedure; obtaining a pharmacy assessment record associated with the patient, the pharmacy assessment record including a medical condition of the patient; using the HCP assessment record to determine whether the patient is authorized to receive a prescription authorization authorizing the use of a prescription medication; as well as When the patient is authorized to receive the prescribed medication: using the pharmacy assessment record to determine whether the pharmacy is authorized to dispense the prescription medication to the patient; as well as When the pharmacy is authorized to dispense the prescribed medication to the patient: Generate dispensing authorizations; and The dispensing authorization is transmitted to the pharmacy.

210. The method of any preceding claim, wherein the procedural results include echocardiographic results.

211. The method of any preceding claim, wherein at least one of the HCP assessment record and the pharmacy assessment record includes potential drug-drug interactions.

212. A method as described in any preceding claim, wherein obtaining the HCP assessment record includes retrieving the HCP assessment record from a database remote from the data processing hardware.

213. The method of any preceding claim, wherein determining whether the patient is authorized to receive the prescription authorization is in response to receiving a prescription request.

214. The method of any preceding claim, wherein the dispensing authorization comprises: the amount of the prescribed medication that the patient is authorized to receive; as well as The time period during which the patient is authorized to receive the prescribed medication.

215. The method of any preceding claim, wherein the operations further comprise, after the period of time has elapsed: determining whether updated procedural results relevant to the patient are available; updating the dispensing authorization using the updated procedure results when the updated procedure results are available; as well as When the updated procedure result is not available, renewing the dispensing authorization is denied.

216. The method of any preceding claim, wherein updating the dispensing authorization comprises at least one of: adjusting the amount of the prescribed medication that the patient is authorized to receive; and The time period during which the patient is authorized to receive the prescribed medication is adjusted.

217. The method of any preceding claim, wherein the operation further comprises generating a report for a regulatory agency when the patient is not authorized to receive the prescribed medication or when the pharmacy is not authorized to dispense the prescribed medication to the patient.

218. The method of any preceding claim, wherein the prescription medication comprises Mavaketal.

219. A system comprising: Data processing hardware; as well as Memory hardware in communication with the data processing hardware, the memory hardware storing instructions which, when executed on the data processing hardware, cause the data processing hardware to perform the operations of any one of method claims 209-218.

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